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Related Collections Neoplasia Oncogenes and Tumor Suppressors Review Articles Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 96 No. 1 (July 1), 2000: pp. 24-33 REVIEW ARTICLE Biological and therapeutic aspects of infant leukemia Andrea Biondi, Giuseppe Cimino, Rob Pieters, and Ching-Hon Pui From Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università Milano-Bicocca, Monza, Italy; Dipartimento di Biotecnologie Cellulari ed Ematologia, Università degli Studi "La Sapienza," Rome, Italy; University Hospital Rotterdam/Sophia Children's Hospital, Rotterdam, The Netherlands; St. Jude Children's Research Hospital and University of Tennessee, Memphis, College of Medicine, Memphis, TN.     Introduction Top Introduction Epidemiology ALL1/MLL/HRX cloning,... Possible mechanisms of aberrant... Why are infant leukemias... Have treatment results for... Acknowledgments References Leukemias diagnosed in the first 12 months of life are characterized by an equal distribution of lymphoid and myeloid subtypes and account for 2.5% to 5% of acute lymphoblastic leukemias (ALLs) and 6% to 14% of acute myeloid leukemias (AMLs) of childhood.1,2 In contrast to an excess of boys among older children with leukemia, there is a slight female predominance among infants with this disease.3-5 Infant leukemias display unique biological and clinical features that have provided important insights into the mechanisms governing normal and aberrant hemopoiesis in the fetus and young children, as well as reasons for the increased rates of treatment failure in infants as compared with older children. This review summarizes recent progress in understanding the biology of infant leukemias and the prospects for better treatment.     Epidemiology Top Introduction Epidemiology ALL1/MLL/HRX cloning,... Possible mechanisms of aberrant... Why are infant leukemias... Have treatment results for... Acknowledgments References The risk of leukemia in children, as in cancer patients in general, reflects a complex interplay between inherited predisposition, exogenous exposures to agents with leukemogenic potential, and chance events. Infant leukemias afford unique investigative models for the study of leukemogenesis. Despite the fact that such leukemias arise very early in life, the leukemogenic contribution of abnormal alleles (transmission of parental mutations) is generally assumed to be small. Familial clustering is not seen in the infant leukemias, and constitutional predisposing alleles have not been identified. However, new germinal mutations in 1 parent could affect a single predisposed offspring if the alterations occur downstream in the spermatogenetic/oogenic pathway; reciprocal translocations that target cells of the developing hemopoietic system could also play a role.6 Infant leukemias have been associated with Down syndrome,7 with Turner syndrome, and with trisomy 9.8 In contrast to other cases, some infant leukemias associated with Down syndrome undergo spontaneous remission.7 These proliferations have distinguishing morphologic, immunophenotypic, and cytogenetic features.9 Infants with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) usually have acquired ALL1/MLL/HRX gene fusions as the major consistent genetic abnormality (see "ALL1/MLL/HRX cloning, structure, and function: clues to pathogenesis?"). Epidemiological and molecular genetic studies demonstrate that most, if not all, cases of infant leukemia arise in utero. First, infant leukemias exhibit fetal-type DJH joining sequences in the immunoglobulin gene.10 Second, the very early onset of some cases with 11q23 chromosomal rearrangements strongly suggests a prenatal leukemogenic event.11 In fact, a report of fetal death due to AML with an ALL1/MLL/HRX rearrangement provided direct evidence of oncogenesis in utero.12 Third, molecular studies of identical twins with leukemias harboring ALL1/MLL/HRX-rearranged genes have corroborated suggestions that ALL1/MLL/HRX rearrangement is acquired in utero. Indeed, the detection of an identical clonal, nonconstitutional rearrangement of the ALL1/MLL/HRX gene in the leukemic cells of both twins provided evidence for a single clonal event in utero in 1 twin, generating leukemic clonogenic progeny that metastasized to the other twin through placental anastomoses or by crossing the maternal circulation and reaching the second twin.13-17 Finally, the same clonotypic ALL1/MLL/HRX-AF4 genomic fusion sequences have recently been backtracked to neonatal blood spots from individuals who were diagnosed with ALL at ages 51 months to 2 years.18 The fetal origin of leukemia has also been established in older children (up to 14 years old) with T-cell ALL or B-precursor cell ALL with TEL-AML1 fusion by studies of monozygotic twin pairs19-21 or neonatal blood spots (Guthrie cards).22 One interpretation of this finding is that many childhood leukemias are initiated by a mutagenic event in utero. The presence of ALL1/MLL/HRX fusion in a susceptible cell type appears sufficient to induce leukemia, whereas with other genetic alterations, additional postnatal mutations are required. It is also likely that ALL1/MLL/HRX fusion occurs more frequently during fetal development, accounting for the high incidence of this genetic abnormality in infants with leukemia. The types of exposures that give rise to leukemogenic somatic genetic changes in utero can be assessed with greater precision in infants than in older children. Thus, maternal alcohol consumption, but not smoking, during pregnancy has been correlated with an increased risk of infant leukemia, especially AML.23,24 It was postulated that ethanol induces microsomal enzymes, such as cytochrome P450, which in turn activate precarcinogens.25 Most studies have shown that an increased incidence of high birth weights and a low incidence of low birth weights correlate with higher rates of infant ALL and AML.26-31 It was suggested that high levels of insulinlike growth factor-1 might produce large babies and contribute to leukemogenesis, an interesting theory that remains to be proved.26 An increased maternal consumption of DNA topoisomerase-II-inhibitor-containing foods, such as specific fruits and vegetables that contain quercetin; soybeans (genistein); tea, cocoa, and wine (catechins); and caffeine have all been related to an increased risk of infant AML.32-34 ALL1/MLL/HRX gene rearrangements are common in secondary acute leukemia (usually with monoblastic or myelomonoblastic morphology) arising after exposure to an epipodophyllotoxin or an anthyacycline, both of which inhibit topoisomerase-II.35,36 This observation supports the theory that exposure of pregnant women to substances that inhibit topoisomerase-II might be a critical event in the development of leukemia in infancy. Anticancer drugs, quinolone antibiotics, flavonoids, catechins, podophylline resin, benzene metabolites, and estrogens can all inhibit topoisomerase-II in vivo or in vitro and may be considered potential mutagens in the induction of acute leukemias with rearranged ALL1/MLL/HRX genes.37 Exposures of the pregnant mother and fetus to dietary, medical, and environmental chemicals that interact with topoisomerase-II may be order-of-magnitude lower in functional doses than in exposures to drugs used in cancer chemotherapy, even though the first class of agents are as biologically active as the latter class.38 It has been proposed that interindividual pharmacogenetic-based differences in metabolism between these types of chemicals might play an important role in dose-response relationships that modulate the risk of pediatric leukemia. Thus, ALL1/MLL/HRX rearrangement has been correlated with low NAD(P)H quinone oxidoreductase (NQO1) activity,39 the quinone moiety being shared by many topoisomerase-II-inhibiting drugs and other chemicals.40-42 Some of the different maternal exposures during pregnancy that have been implicated in the genesis of infant leukemia could therefore operate via the quinone metabolic pathway. The possible role of parental genetic susceptibility factors in modulating the effects of parental carcinogen exposure was recently suggested by studies of glutathione-S-transferase (GST) genes polymorphisms in parents of diseased infants. Among the parents of infants with leukemias lacking ALL1/MLL/HRX gene rearrangements, the frequencies of single and double GST genes (class M-GSTM; class T-GSTT) deletions were significantly higher than expected. The deletion of both GSST1 and GSTM1 genes in either parent may therefore affect the risk of infant leukemia through a pathway independent of the ALL1/MLL/HRX gene.43 Whether parental preconceptional or in utero exposure to radiation increases the risk of infant leukemia remains controversial. One report suggests that there might have been a transient increase in infant leukemia in northern Greece in association with radioactive fallout from the Chernobyl accident.44 However, the European Childhood Leukemia-Lymphoma Incidence Study failed to show any increase in the incidence of childhood leukemia as a consequence of this event.45 Likewise, in a subsequent study, German investigations were not able to correlate an increased incidence of infant leukemia with ionizing radiation from the accident.46     ALL1/MLL/HRX cloning, structure, and function: clues to pathogenesis? Top Introduction Epidemiology ALL1/MLL/HRX cloning,... Possible mechanisms of aberrant... Why are infant leukemias... Have treatment results for... Acknowledgments References The ALL1/MLL/HRX gene, located at cytogenetic band 11q23, is consistently altered in infant acute leukemia, being rearranged in more than 60% to 70% of cases.1,2 This gene was identified in 1991 and completely cloned and characterized in 1992. Somatic cell-hybrids or fluorescent in situ hybridization (FISH) was used to map the chromosomal 11q23 breakpoints into a region between the CD3 and the porhobilinogen deaminase genes. Subsequently, a yeast artificial chromosome (YAC), containing the CD3 gene was cloned and shown by FISH analysis to span the t(4;11), t(6;11), t(9;11), and t(11;19) chromosomal translocation breakpoints.47 When a similar YAC was used, a DNA insert was obtained in which Southern blot analysis detected rearranged bands in leukemic cells from patients with t(1;11), t(4;11), t(6;11), t(9;11), t(10;11), and del(11q23) abnormalities. Breakpoints were clustered in a small region of 8 kilobases (kb) within a gene named ALL1 by Cimino et al48 because rearrangements were first identified in a patient with ALL. Other investigators completed characterization of the gene and added the designation MLL because the gene could be altered in myeloid or lymphoid leukemias, and the designations HRX or Hrtx1 to indicate homology with the trithorax (trx) gene of Drosophila.47,49-51 ALL1/MLL/HRX spans approximately 90 kb of DNA, encodes a major transcript of 15 kb, and consists of 36 exons, ranging in size from 65 to 4249 base pairs. The protein product consists of more than 3910 amino acids containing 3 regions homologous to sequences of the Drosophila trx gene, including cysteine-rich regions that can fold into 6 zinc-finger-like domains and a highly conserved 200-amino acid SET domain located at the carboxyl-terminal end.49-56 In Drosophila, the trx gene acts to spatially maintain restricted expression pattern of the Antennapoedia and Bithorax complexes during fruit fly development. trx activates transcription of multiple genes of the 2 complexes and, thus, counteracts the activity of Polycomb group (PcG) genes, which repress the transcription of the same genes. Gene-targeting studies demonstrated that ALL1/MLL/HRX is also a positive regulator of Hox genes in mice.57 Hox expression is shifted posteriorly in ALL1/MLL/HRX heterozygous (+/) embryos and completely abolished in ALL1/MLL/HRX homozygous null (/) embryos. Shifts in Hox expression are also observed in mice with targeted mutations in PcG.58,59 More recently, Yu et al60 showed that mice with deletions of the ALL1/MLL/HRX gene had altered maintenance rather than activation of the Hox gene. The ALL1/MLL/HRX gene product possesses 2 other regions that could be directly or indirectly involved in the control of gene transcription. These are (1) a region that is similar to the AT hook of high-mobility-group-I proteins and that binds to AT-rich regions of the minor groove of the DNA and (2) a cysteine-rich region homologous to the mammalian DNA methyltransferase double helix, which by favoring conformational DNA changes, facilitates the action of other regulatory genes.49-51 To date, at least 16 different fusion partner genes involved in chromosomal translocations with ALL1/MLL/HRX have been characterized (Table 1).61-77 Additionally, internal duplications within the amino-terminal part of ALL1/MLL/HRX and specific deletions of exon 8 have been detected in leukemic blast cells of some leukemia patients 78-80                                View this table: [in this window] [in a new window]   Table 1. Structural characteristics, location, and putative functions of ALL1/MLL/HRX partner genes The impressive heterogeneity of ALL1/MLL/HRX recombination raises difficult questions as to how fusion proteins cause leukemia and the role of partner genes in activating the ALL1/MLL/HRX gene and determining the leukemic phenotype. Thus, several investigators have searched for structural similarities among the different ALL1/MLL/HRX partner genes. With the exception of the homology shown by AF9 with ENL, by AF10 with AF17, by AFX with AF6q21, and by MSF with hCDCrel, sequence analysis did not reveal structural or functional similarities. Thus, it is unlikely that these fusion partners could play a role in the function of the hybrid gene by simply providing transcriptional modulation (activation or repression) domains. By contrast, the active functional contribution of partner genes in determining the oncogenic capacityof the resulting hybrid gene is strongly suggested by several observations. All partner genes are fused in frame to ALL1/MLL/HRX, generating a full-length fusion protein, whereas terminal deletions of ALL1/MLL/HRX have not been identified in leukemic cells. In addition, by testing a series of ALL1/MLL/HRX-ENL mutants to investigate the participation of several conserved sequence motifs in the oncogenic activity of the fusion product, Slany et al81 recently demonstrated that the DNA binding motifs of ALL1/MLL/HRX, as well as the transcriptional transactivation activity of ENL, are required for in vitro immortalization of murine myeloid cells. Finally, knock-in mice expressing an ALL1/MLL/HRX-AF9 fusion gene under the control of the natural ALL1/MLL/HRX promoter developed AML, while mice expressing an ALL1/MLL/HRX/Myc tag fusion gene remained free of leukemia.82 Despite extensive studies, it is still unclear as to how fusion products participate in leukemogenesis. One possibility is that they might supply a dimerization domain, which could activate the ALL1/MLL/HRX chimeric genes. This hypothesis is supported, first, by the observation that several ALL1/MLL/HRX partner genes possess structures involved in the protein-protein interactions and, second, by the finding that the novel self-fusion genetic mechanism mentioned above leads to internal duplication of the amino-terminal part of the ALL1/MLL/HRX gene, which functionally could be equivalent to a dimer of the NH2 portion of the ALL1/MLL/HRX. Since the RNA polymerase elongation factor ELL and the transcriptional coactivator CBP (gene for CREB binding protein) are 2 ALL1/MLL/HRX fusion partners involved in transcriptional regulation, an interaction of the ALL1/MLL/HRX fusion genes with the RNA polymerase-II transcription machinery has been proposed. Of all the ALL1/MLL/HRX motifs present in all the fusion proteins, the AT hook region is the best characterized, and several lines of evidence suggest that this region has an important role in targeting and regulating transcriptional units for normal hematopoietic growth and differentiation. In this respect, it has been suggested that the Trx protein maintains target genes in a transcriptionally active state by an epigenetic mechanism that probably involves chromatin remodeling. Although ALL1/MLL/HRX has not been shown to remodel chromatin, the carboxy-terminal SET domain of ALL1/MLL/HRX interacts with hSNT5/INI1, a component of the SNF/SWI complex, a chromatin-remodeling system.83,84 Importantly, the SET domain is lost when the aminoterminus of the ALL1/MLL/HRX and the carboxyl-terminal partner residues fuse to form ALL1/MLL/HRX fusion protein. The loss of this domain may explain the down-regulation of the ARP1 gene in embryonic stem cells from ALL1/MLL/HRX double-knockout mice, as ARP1 was recently identified and characterized as a target of ALL1/MLL/HRX.85 Finally, Adler et al86 have shown that the GADD34 gene, which encodes a DNA damage-inducible factor, is another target of ALL1/MLL/HRX. These authors also showed that, while ALL1/MLL/HRX protein interacts directly with GADD34, resulting in a significant increase in apoptosis after treatment with ionizing radiation, the coexpression of 3 different ALL1/MLL/HRX fusion proteins (ie, ALL1/MLL/HRX-ENL, ALL1/MLL/HRX-AF9, and ALL1/MLL/HRX-ELL) had an antiapoptotic effect, abrogating GADD34-induced apoptosis. The authors also observed a difference between wild-type and leukemic ALL1/MLL/HRX fusion proteins, leading them to postulate a gain of function for ALL1/MLL/HRX compared with the wild-type protein, suggesting that the inhibition of apoptosis may be relevant to leukemogenesis.86 With regard to the precise function of the wild-type ALL1/MLL/HRX protein, Hess et al,87 after examining the effects of the haploinsufficiency or absence of ALL1/MLL/HRX on the in vitro differentiation of yolk sac progenitor cells, concluded that ALL1/MLL/HRX is required for the generation of normal numbers of hematopoietic progenitors and their proper differentiation, especially along the granulocytic and monocytic lineages.     Possible mechanisms of aberrant ALL1/MLL/HRX1 recombination Top Introduction Epidemiology ALL1/MLL/HRX cloning,... Possible mechanisms of aberrant... Why are infant leukemias... Have treatment results for... Acknowledgments References Chromosomal translocations leading to oncogene activation are common events in the pathogenesis of leukemia, but the molecular basis for this process is still incompletely understood. ALL1/MLL/HRX1 offers a useful model for elucidating such mechanisms. First, the gene is altered by promiscuous chromosomal recombination with a variety of partner genes in various subsets of acute leukemias, including some childhood and adult acute lymphoid or myeloid leukemias, secondary leukemias associated with prior exposure to drugs that target topoisomerase-II (etoposide, tenoposide, and anthracyclines), and, especially, infant leukemias.88-92 Second, several DNA motifs implicated in DNA-recombination mechanisms have been recently identified and localized within the ALL1/MLL/HRX1 breakpoint cluster region (bcr). These include (1) recombinase signal sequences (heptamers and nonamers); (2) scaffold attachment regions (SARs); (3) high-affinity topoisomerase-II-binding sites, including a strong site in exon 9; and (4) Alu sequences.93-95 By comparing ALL1/MLL/HRX rearrangements in de novo versus therapy-related acute leukemias, Broeker et al93 identified statistically significant differences in the breakpoint distribution between the 2 groups. In particular, they found that in therapy-related acute leukemias, the breakpoints clustered in the telomeric portion of the ALL1 bcr, which is characterized by the presence of SARs and high-affinity topoisomerase-II binding sites, in contrast to cases of de novo leukemias, whose breakpoints in most instances clustered in the centromeric or 5' bcr. On the basis of these observations, the authors suggested that the mechanisms of translocation in de novo and treatment-related leukemias secondary to treatment with topoisomerase-II inhibitors might be different.93 This conclusion has important implications for attempts to understand the etiology and pathogenesis of infant leukemias. Molecular analyses of ALL1/MLL/HRX rearrangements in infant twins showed that these genetic aberrations arise during fetal hemopoiesis in utero.13 Epidemiologic evidence has also indicated that certain conditions during pregnancy, such as exposure to drugs, alcohol, and pesticides, are associated with an increased risk of infant leukemia.96,97 Therefore, one mechanism leading to ALL1/MLL/HRX translocations might be chromosomal breakage induced by topoisomerase-II inhibitors within the ALL1/MLL/HRX gene, while another could be represented by mistakes in DNA-repair mechanisms. This hypothesis is supported by recent observations by Aplan et al98 showing that topoisomerase-II-inhibiting drugs cleave double-stranded DNA at a site in ALL1/MLL/HRX exon 9 both in vivo and in vitro. More recently, Gillert et al99 implicated "error-prone repair" as the DNA-repair process leading to ALL1/MLL/HRX translocations. From these considerations and from analogy with the involvement of the ALL1/MLL/HRX gene in treatment-related leukemia, it was suggested that the critical leukemogenic event(s) occurring in utero might similarly involve prenatal exposure to topoisomerase-II inhibitors as represented by several natural and medicinal substances. That infant leukemias and topoisomerase-II-related secondary leukemias show the same biased distribution of ALL1/MLL/HRX breaks100 lends credence to this hypothesis. A substantial list of candidate leukemogenic agents are under investigation in international case-control epidemiological studies.     Why are infant leukemias so different? Top Introduction Epidemiology ALL1/MLL/HRX cloning,... Possible mechanisms of aberrant... Why are infant leukemias... Have treatment results for... Acknowledgments References Clinical and biological features ALL of infancy is associated with a high leukocyte count at presentation, hepatosplenomegaly, and central nervous system (CNS) involvement.1,101,102 The immunophenotype is usually that of immature B-lineage precursors and is characterized by a lack of CD10 expression and the coexpression of myeloid-associated antigens. A high frequency of myeloperoxidase-gene expression typifies infant ALL.103 These findings suggest that the classic form of infant ALL originates in a stem cell that has not fully committed to lymphoid differentiation. This hypothesis is supported by the observation that multipotential stem and progenitor cells prime the commitment and differentiation of several different hematopoietic lineages.104 The frequency of ALL1/MLL/HRX gene rearrangements is very high, possibly as high as 75% when studied with molecular techniques,1,2 as would be predicted from the frequency of the t(4;11), the translocation most often involved in the generation of this fusion gene. These 3 characteristicslack of CD10 expression, expression of myeloid-associated markers, and ALL1/MLL/HRX gene rearrangementsare correlated with one another, and their presence is inversely related to the age of the infant.2,102,105-111 For example, ALL1/MLL/HRX rearrangement is associated with 90% of the CD10 cases, contrasted with only 20% of the CD10+ cases.109,110,112 Among infants, a lack of CD10 expression, coexpression of myeloid-associated markers, ALL1/MLL/HRX rearrangement, and age of less than 6 months are associated with a poor prognosis.2,101,102,105-107,109-115 The event-free survival of infants with CD10 B-precursor-cell ALL is only about 25%, as compared with 50% to 55% for those with the CD10+ phenotype.102,106,113 Similar estimates apply to cases with an ALL1/MLL/HRX rearrangement: 10% to 20% as compared with 50% in cases with ALL1/MLL/HRX in a germ-line configuration.102,107,109-111,115 Two studies105,111 have analyzed the relation between myeloid-associated antigen expression and outcome in infant ALL: the event-free survival in cases expressing the antigens was 0% to 10%, compared with about 60% in the other cases. Finally, age itself can be used as a prognostic factor in infant ALL. Infants younger than 6 months of age have a worse outcome (10% to 20% event-free survival) than do infants between 6 and 12 months of age at diagnosis (40% to 45% event-free survival).102,106,107,111 The above-mentioned high-risk factors are closely interrelated. In several analyses, the ALL1/MLL/HRX rearrangement emerged as an important adverse prognostic factor.109,114-117 In one large multivariate analysis, it was shown that ALL1/MLL/HRX rearrangement, age, CD10, and white blood cell count were all independent prognostic factors.115 Two other small studies showed that the ALL1/MLL/HRX rearrangement was of prognostic relevance independent of the white blood cell count.109,114 Recent studies by the Childrens Cancer Group (CCG) suggested that the t(4;11) is the only ALL1/MLL/HRX-related translocation associated with a dismal outcome.107,112,118 In a combined Pediatric Oncology Group (POG)-St. Jude study, infant ALL cases with ALL1/MLL/HRX-ENL fusion due to the t(11;19) had an extremely poor prognosis.119 However, the adverse outcome cannot be attributed solely to the t(4;11) or the t(11;19), as children 1 to 9 years old with this abnormality have a reasonably favorable prognosis.119-121 Thus, other factors must contribute to the generally poor treatment results obtained in infants. In a recent study by the Berlin-Frankfurt-Münster (BFM) group, a poor early-treatment response to prednisone was found to be the strongest predictor of outcome in infant ALL, even in the subgroup with the t(4;11).122 Hence, a poor early-prednisone response is being used as the sole criterion for allogenic, hematopoietic stem cell transplantation in the Interfant '99 study of infant ALL, conducted by a consortium of European and US investigators. In AML, age and the presence of 11q23 abnormalities have no clear adverse prognostic impact.1,111,123,124 Infant AML is characterized by myelomonoblastic or monoblastic morphology, a high percentage of CNS involvement, and a high leukocyte count. ALL1/MLL/HRX rearrangements are found in about 60% of infant AML cases.111,125 The prognostic factors that define infant AML are not clearly defined. In a St. Jude study, high presenting leukocyte counts and male sex were the only 2 independent adverse prognostic factors.111 The association of high leukocyte counts with a poor outcome is not unexpected; however, the basis for the predictive strength of male sex is uncertain. Lie et al126 have also found male gender to be a predictor of a poor outcome. The prognostic impact of M4 and M5 morphology is controversial, probably owing to the use of different treatment regimens.111,127 In a recent St. Jude study, the presence of the t(9;11)(p22;q22) conferred a favorable prognosis.128 Clearly, additional studies are needed to ascertain the prognostic factors in infant AML. Drug-resistance profile Age, immunophenotype, and ALL1/MLL/HRX rearrangement reflect or cause differences in drug-resistance factors. These can be pharmacokinetic factors that determine the amount of drugs to which the leukemic cells are exposed or differences in cellular pharmacodynamics that determine the sensitivity of the cells to the drugs. There are no data suggesting that pharmacokinetic resistance might explain the poorer outcome of infant ALL; infants simply do not show increased clearance of antileukemic drugs. Nonetheless, some studies suggest differences at the cellular level. Kumagai et al129 showed that leukemic cells from infants with 11q23 rearrangements grow better on stromal layers in vitro than do cells from other cases. Uckun et al130 similarly showed that cells from infants with ALL1/MLL/HRX-rearranged ALL are more readily recovered from severe combined immunodeficiency (SCID) mice than are cells from children with other types of ALL. In related studies, Kersey at al131 found that leukemic cells with the t(4;11) are more resistant to stress-induced death than are other B-lineage blast cells, while Pieters et al132 showed that cells from infants with ALL are significantly more resistant in vitro to prednisolone and L-asparaginase than are cells from older children. In vitro resistance to these drugs is a strong adverse prognostic factor.133-135 Of considerable therapeutic interest, the leukemic cells of infants with ALL are significantly more sensitive to cytarabine than are cells from older children.132 In addition, B-cell precursors that lacked CD10 expression were resistant to prednisone and L-asparaginase but showed significant sensitivity to cytarabine, in contrast to cases with CD10 expression. A study by the Dana-Farber Cancer Institute Consortium showed that high-dose cytarabine given immediately after remission induction is a feasible strategy and might benefit infants with ALL.136 Recent data from a German study of adult ALL patients showed that the long-term survival of adults with pro-B ALL with the t(4;11) has increased to about 40% with the introduction of high-dose cytarabine/mitoxantrone consolidation therapy.137 Finally, Reiter et al108 reported that infants with ALL more frequently show a poor in vivo response to prednisone than do older children. In their study, age lost its prognostic value in a multivariate analysis because of its association with a poor prednisone response in vivo. A recent update of the BFM 1986 and 1990 studies confirmed the prognostic significance of the steroid response: the 6-year event-free survival for infants with a good prednisone response was 58% versus only 16% for infants with a poor prednisone response.122 Differences between infants and older children Rapid changes in physiologic processes govern drug disposition in infants, especially neonates. First, the total body water content as a percentage of total body weight decreases from 75% in the newborn period to 60% at 1 year and 55% by adulthood; extracellular water as a percentage of total body water decreases from 45% in the neonate to 20% in the adult.138 Second, many drugs bind less avidly to serum proteins in the neonate than in the adult, leading to an increase in the unbound fraction (presumably the active drugs) and potentially enhanced pharmacologic responses in the former age group.139 Third, the activity of many P-450 enzymes is low during infancy.140,141 This decreased metabolic activity could result in reduced cytotoxic effects of antineoplastic drugs that require bioactivation (eg, cyclophosphamide) or in enhanced cytotoxicity of those that undergo inactivation (eg, vincristine and daunorubicin). Fourth, renal tubular function and the glomerular filtration rate reach adult levels by 7 months and 5 months of age, respectively142,143; hence, any drugs that depend on renal function for clearance will have increased systemic exposure and pharmacologic effects in infants. There are, in addition, many important anatomical differences by age. For example, the volume of the CNS relative to body surface area or body weight is much larger in young children than in adults. While the CNS volume in infants approaches 80% to 90% of the adult value by age 4 to 6 years, body surface area does not reach adult values until approximately 16 to 18 years of age.144 Indeed, Bleyer144 demonstrated that the dosage of intrathecal chemotherapy should be based on age rather than body surface area to avoid undertreatment in young children. Another major age difference is the ratio of body weight (kg) to body surface area (m2); for example, the ratio for neonates is 18, which is lower than the ratio of 25 in 5-year-olds, which in turn is a lower value than the value of 40 in adults.145 Thus, if drug dosage were based solely on body weight for all age groups, infants would receive a substantially lower dosage by body surface area than would other children. Whether the dosage of any given drug in infants should be based on body surface area or body weight remains in question. This uncertainty is well illustrated by the empirical approach to drug dosing in different clinical trials of infant leukemias, some based entirely on body weight, others on body surface area, and still others on body surface area adjusted by age (ie, proportionally lower in young infants). There are only limited pharmacokinetic and pharmacodynamic data on individual antileukemic drugs and on the tolerance to these agents in infants. An early report suggested that infants with leukemia are more susceptible to severe vincristine neurotoxicity than are children.146 In a subsequent study of remission-induction therapy with vincristine (1.5 mg/m2), prednisone, L-asparaginase, and intrathecal methotrexate, 7 of the 9 patients with a body surface area less than 0.5 m2 developed vincristine neurotoxicity, which was severe in 4.147 It was uncertain whether L-asparaginase or methotrexate contributed to increased toxicity by altering hepatic function or whether the infant nervous system is more sensitive to vincristine. Because infants have a large body surface area relative to body weight, the authors proposed that the drug doses in infants should be calculated on the basis of body weight (in kilograms), with dosages normalized from those of body surface area (dividing by 30). This conversion effectively lowers the final dosage and has proved adequate for vincristine treatment in infants. Limited data suggest that dosing of teniposide, etoposide, and cytarabine based on body surface area would yield similar systemic exposure in infants and adults.145 By contrast, normalized dosing of doxorubicin by body weight was more likely to achieve similar systemic exposure in these 2 age groups. The study also showed that methotrexate clearance tended to be lower in infants, but there was no need to reduce dosage, as methotrexate was better tolerated in these patients. Thus, uniform rules for dosage adjustment of all antileukemic agents used in infants is inappropriate; additional pharmacokinetic and pharmacodynamic studies are needed in infants younger than 2 months of age.     Have treatment results for infant leukemias improved? Top Introduction Epidemiology ALL1/MLL/HRX cloning,... Possible mechanisms of aberrant... Why are infant leukemias... Have treatment results for... Acknowledgments References Acute lymphoblastic leukemia Contemporary treatment for childhood ALL has cured approximately 80% of patients in some clinical trials,148 but results for infant ALL are still suboptimal. A variety of treatment regimens have been tested in infants, generally yielding event-free survival rates of 20% to 35% (Table 2).101,102,106,122,132,136,149-154 (See also A. Biondi, unpublished data, 1999.) In several recent clinical trials, high-dose methotrexate, high-dose cytarabine, and intensive consolidation/reinduction therapy appear to have improved clinical outcome,106,112,122,136,153 but these results should be viewed as preliminary because of the small numbers of patients enrolled, the lack of randomization, and the disproportionate numbers of cases with high-risk disease (ie, ALL1/MLL/HRX-AF4 fusion). Moreover, the efficacy of any treatment component is affected by the overall therapeutic strategy. Hence, while clinical trials incorporating high-dose methotrexate with or without cytarabine have generally yielded improved results, 1 study with a similar therapeutic strategy resulted in an inferior outcome, partly because of an increase in remission deaths from infection or gastrointestinal complications due to combination treatment with etoposide and high-dose cytarabine.102 Likewise, excessive toxicities and treatment-related deaths, presumably due to high-dose daunorubicin in very young infants, were encountered in a POG study, despite encouraging overall results.153 Both studies underscore the need for pharmacokinetic and pharmacodynamic studies to ensure optimal dosing in infants.                                View this table: [in this window] [in a new window]   Table 2. Treatment regimens and results for infants with ALL Neuropsychological abnormalities are well-recognized complications of cranial irradiation, especially in very young children. Severe neurological deficits and learning disabilities were observed in 4 of 8, in 9 of 11, and in 2 of 4 long-term survivors of infant ALL who had received cranial irradiation in 3 separate studies.101,106,136 By contrast, in another study, infants who did not receive cranial irradiation showed normal neuropsychological development when tested at 5 years of age.155 In virtually all studies, attempts have been made to reduce neuropsychological complications by reducing the dosage of cranial irradiations, delaying the radiotherapy until the child was more than 1 year old, or avoiding irradiation altogether (Table 2). To date, most investigators favor eliminating irradiation in all infants with ALL, even in those with CNS leukemia at diagnosis, relying instead on intensive systemic and intrathecal treatments. Several observations support this approach. First, in the early studies of the CCG, cranial irradiation had no impact on treatment outcome.101 Second, in the recent CCG-1883 trial, which did not include cranial irradiation, the cumulative risk of isolated CNS relapse was only 3% ± 2%,112 despite a 14.2% prevalence of CNS leukemia at diagnosis. Third, in a POG study that employed only intrathecal treatment of the CNS for all patients, failure rates were similar in infant cases with and without CNS leukemia at diagnosis.152 In fact, none of the 21 patients with CNS leukemia at diagnosis had CNS involvement at the time of relapse. There is a paucity of data on allogeneic hematopoietic stem-cell transplantation in infants with ALL. Two limited collaborative group studies have yielded dismal results: only 2 of 11 and none of 3 patients survived.102,112 The experience of the Fred Hutchinson Cancer Research Center is more encouraging, with 7 of 9 infants alive in first remission for 2 to 11 years after allogeneic transplantation.156 Additional studies are clearly needed to determine the role of hematopoietic stem-cell transplantation in high-risk infant cases. Acute myeloid leukemia While infants with ALL are treated on separate protocols in most clinical trials, those with AML receive essentially the same therapy as older children in virtually all studies.1,126,157-166 Infants with acute monoblastic leukemia are sometimes treated with epipodophyllotoxin-containing regimens,167 apparently because of the increased sensitivity of their leukemic cells to this class of agents.168,169 In most clinical trials of AML therapy, event-free survival rates are similar for infants and older children.126,157-160,164,165 In the BFM 1983 and 1987 trials, children younger than 2 years had an inferior treatment outcome, as compared with older children.166 However, in multivariate analyses, age lacked independent significance after adjustment for the FAB M5 or M7 subtypes, hyperleukocytosis, and an unfavorable karyotype. In the POG 8498 study, children younger than 2 years had a more favorable outcome than did older children.161 The inclusion of children 1 to 2 years of age made it difficult to determine the prognosis for infants younger than 12 months. Since treatment outcome generally does not differ by age group in childhood AML, there is no compelling reason to develop separate trials for infant AML, with the following exception. Infants with megakaryoblastic leukemia and the t(1;22) (p13;q13) appear to have a particularly poor prognosis170,171 and may be candidates for innovative experimental therapy or perhaps allogeneic hematopoietic stem-cell transplantation. Although the latter procedure has yielded long-term survival in some infant cases,3,172,173 its relative efficacy compared with contemporary intensive chemotherapy is unknown owing to the lack of randomized studies. Ongoing clinical trials Currently, 2 large international prospective studies for the treatment of infant ALL are under way. One is a collaborative US study conducted by the POG and CCG. The other is a large international effort, Interfant '99, by European and US study groups. The POG/CCG trial tests the feasibility and efficacy of intensive therapy. Infants with an ALL1/MLL/HRX rearrangement are eligible for allogeneic hematopoietic stem-cell transplantation. The Interfant '99 protocol is based on a so-called hybrid form of therapy, consisting of elements from both ALL and AML treatments administered on an ALL-like schedule and combining both low-dose and high-dose cytarabine. Only patients with a poor initial response to prednisone are eligible for hematopoietic stem-cell transplantation. No CNS or total-body irradiation is used, and anthracyclines, epipodophyllotoxins, and alkylating agents are either avoided or used only sparingly. Both studies will prospectively analyze whether age, immunophenotype, leukocyte count, initial response to therapy, and ALL1/MLL/HRX rearrangement have independent prognostic value. Conclusion In most cases of infant ALL and AML, the discovery of ALL1/MLL/HRX gene involvement opened new opportunities for molecular diagnosis and monitoring, molecular epidemiology, and studies to unravel basic biologic mechanisms. Continued molecular investigations are needed to gain further insight into the basic differences between leukemias in infants and older children. Current therapy for infant ALL and AML is inadequate. Although intensification of chemotherapy and wider use of allogeneic hematopoietic stem-cell transplantation could improve this situation, there remains an urgent need to develop novel therapies by exploiting the unusual biologic properties of leukemic progenitor cells expressing the abnormal ALL1/MLL/HRX gene product.     Acknowledgments Top Introduction Epidemiology ALL1/MLL/HRX cloning,... Possible mechanisms of aberrant... Why are infant leukemias... Have treatment results for... Acknowledgments References We thank E. Paccagnini for secretarial support and J. Gilbert for editorial review.     Footnotes Submitted September 20, 1999; accepted February 24, 2000. Supported by Fondazione M. Tettamanti, Associazione Italiana Ricerca sul Cancro (AIRC), and MURST (A.B.); by the Foundation Pediatric Oncology Center Rotterdam and grants 94-679, 95-921, and 97-1564 from the Dutch Cancer Society (R.P.); and by a Center of Excellence Grant from the State of Tennessee, by the American Lebanese Syrian Associated Charities (ALSAC), and by grants CA51001, CA21765, CA36401, CA78224, CA20180, and CA60419 from the National Institutes of Health (C-H.P). Reprints: Andrea Biondi, Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università Milano-Bicocca, Ospedale S. Gerardo, Via Donizetti, 106, 20052-Monza (MI) Italy; e-mail: fondazione.tettamanti{at}galactica.it. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.     References Top Introduction Epidemiology ALL1/MLL/HRX cloning,... Possible mechanisms of aberrant... Why are infant leukemias... Have treatment results for... Acknowledgments References 1. Pui CH, Kane JR, Crist WM. Biology and treatment of infant leukemia. Leukemia. 1995;9:762-769. 2. Greaves MF. Infant leukemia biology, aetiology and treatment. Leukemia. 1996;10:372-377. 3. Chessells JM. Leukaemia in the young child. Br J Cancer Suppl. 1992;18:S54-S57. 4. Birch JM, Blair V. The epidemiology of infant cancers. Br J Cancer Suppl. 1992;18:S2-S4. 5. Pui CH, Raimondi SC, Murphy SB, Ribeiro RC, Kalwinsky DK, Dahl GV. An analysis of leukemic cell chromosomal features in infants. Blood. 1987;69:1289-1293. 6. Greaves M. A natural history for pediatric acute leukemia. Blood. 1993;82:1043-1051. 7. Rosner F, Lee SL. Down's syndrome and acute leukemia: myloblastic or lymphoblastic? report of forty-three cases and review of the literature. Am J Med. 1972;53:203-218. 8. Van den Berghe H, Fryns JP, Verresen H. Congenital leukaemia with 46, XX, t(Bq+, Cq) cells. J Med Genet. 1972;9:468-470. 9. Litz CE, Davies S, Brunning RD, et al. Acute leukemia and the transient myeloproliferative disorder associated with Down syndrome: morphologic, immunophenotypic and cytogenetic manifestations. Leukemia. 1995;9:1432-1439. 10. Wasserman R, Galili N, Ito Y, Reichard BA, Shane S, Rovera G. Predominance of fetal type DJH joining in young children with B precursor lymphoblastic leukemia as evidence for an in utero transforming event. J Exp Med. 1992;176:1577-1581. 11. Sansone R, Negri D. Cytogenetic features of neonatal leukemias. Cancer Genet Cytogenet. 1992;63:56-61. 12. Hunger SP, McGavran L, Meltesen L, Parker NB, Kassenbrock CK, Bitter MA. Oncogenesis in utero: fetal death due to acute myelogenous leukaemia with an MLL translocation. Br J Haematol. 1998;103:539-542. 13. Ford AM, Ridge SA, Cabrera ME, et al. In utero rearrangements in the trithorax-related oncogene in infant leukaemias. Nature. 1993;363:358-360. 14. Gill Super HJ, Rothberg PG, Kobayashi H, Freeman AI, Diaz MO, Rowley JD. Clonal, nonconstitutional rearrangements of the MLL gene in infant twins with the acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23. Blood. 1994;83:641-644. 15. Mahmoud HH, Ridge SA, Behm FG, et al. Intrauterine monoclonal origin of neonatal concordant acute lymphoblastic leukemia in monozygotic twins. Med Pediatr Oncol. 1995;24:77-81. 16. Campbell M, Cabrera ME, Legues ME, Ridge S, Greaves M. Discordant clinical presentation and outcome in infant twins sharing a common clonal leukaemia. Br J Haematol. 1996;93:166-169. 17. Richkind KE, Loew T, Meisner L, Harris C, Wason D. Identical cytogenetic clones and clonal evolution in pediatric monozygotic twins with acute myeloid leukemia: presymptomatic disease detection by interphase fluorescence in situ hybridization and review of the literature. J Pediatr Hematol Oncol. 1998;20:264-267. 18. Gale KB, Ford AM, Repp R, et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc Natl Acad Sci U S A. 1997;94:13950-13954. 19. Ford AM, Pombo-de-Oliveira MS, McCarthy KP, et al. Monoclonal origin of concordant T-cell malignancy in identical twins. Blood. 1997;89:281-285. 20. Ford AM, Bennett CA, Price CM, Bruin MCA, Van Wering ER, Greaves M. Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. Proc Natl Acad Sci U S A. 1998;95:4584-4588. 21. Wiemels JL, Ford AM, Van Wering R, Postma A, Greaves M. Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1 gene fusion in utero. Blood. 1999;94:1057-1062. 22. Wiemels JL, Cazzaniga G, Daniotti M, et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet. 1999;354:1499-1503. 23. Severson RK, Buckley JD, Woods WG, Benjamin D, Robison LL. Cigarette smoking and alcohol consumption by parents of children with acute myeloid leukemia: an analysis within morphological subgroupsa report from Childrens Cancer Group. Cancer Epidemiol Biomarkers Prev. 1993;5:433-439. 24. van Duijn CM, van Steensel-Moll HA, Coebergh JW, van Zanen GE. Risk factors for childhood acute non-lymphocytic leukemia: an association with maternal alcohol consumption during pregnancy? Cancer Epidemiol Biomarkers Prev. 1994;3:457-460. 25. Shu XO, Ross JA, Pendergrass TW, Reaman GH, Lampkin B, Robison LL. Parental alcohol consumption, cigarette smoking, and risk of infant leukemia: a Childrens Cancer Group study. J Natl Cancer Inst. 1996;88:24-31. 26. Ross JA, Perentesis JP, Robison LL, Davies SM. Big babies and infant leukemia: a role for insulin-like growth factor-1? Cancer Causes Control. 1996;7:553-559. 27. Ross JA, Potter JD, Shu XO, Reaman GH, Lamkin B, Robison LL. Evaluating the relationships among material reproductive history, birth characteristics, and infant leukemia: a report from the Children's Cancer Group. Ann Epidemiol. 1997;7:172-179. 28. Westergaard T, Andersen PK, Pedersen JB, et al. Birth characteristics, sibling patterns and acute leukemia risk in childhood: a population-based cohort study. J Natl Cancer Inst. 1997;89:939-947. 29. Wertelecki W, Mantel N. Increased birthweight in leukemia. Pediatr Res. 1973;7:132-138. 30. Kaye SA, Robison LL, Smithson WA, Gunderson P, King FL, Neglia JP. Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia. Cancer. 1991;68:1351-1355. 31. Cnattingius S, Zack MM, Ekbom A, et al. Prenatal and neonatal risk factors for childhood lymphatic leukemia. J Natl Cancer Inst. 1995;87:908-914. 32. Ross JA, Potter JD, Reaman GH, Pendergrass TW, Robison LL. Maternal exposure to potential inhibitors of DNA topoisomerase-II and infant leukemia (United States): a report from the Children's Cancer Group. Cancer Causes Control. 1996;7:581-590. 33. Ross JA, Potter JD, Robison LL. Infant leukemia, topoisomerase-II inhibitors, and the MLL gene. J Natl Cancer Inst. 1994;86:1678-1680. 34. Ross JA. Maternal diet and infant leukemia: a role for DNA topoisomerase II inhibitors? Int J Cancer Suppl. 1998;11:26-28. 35. Pui CH, Relling MV, Rivera GK, et al. Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia. 1995;9:1990-1996. 36. Rowley J.D. The critical role of chromosome translocations in human leukemias. Annu Rev Genet. 1998;32:495-519. 37. Greaves M. Aetiology of acute leukemia. Lancet. 1997;349:344-349. 38. Yamashita Y, Kawada SZ, Nakano H. Induction of mammalian topoisomerase II dependent DNA cleavage by nonintercalative flavonoids, genistein and orobol. Biochem Pharmacol. 1990;39:737-744. 39. Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF, and the United Kingdom Childhood Cancer Study Investigators. A lack of function NAD(P)H:quinone oxudoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. Cancer Res. 1999;59:4095-4099. 40. Powis G. Free radical formation by antitumor quinones. Free Radic Biol Med. 1989;6:63-101. 41. Chen H, Eastmond DA. Topoisomerase inhibition by phenolic metabolites: a potential mechanism for benzene's clastogenic effects. Carcinogenesis. 1995;16:2301-2307. 42. Frydman B, Marton LJ, Sun JS, et al. Induction of topoisomerase-II mediated DNA cleavage by beta-lactone and related naphthoquinones. Cancer Res. 1997;57:620-627. 43. Biondi A, Garte S, Crosti F, et al. Parental exposure and susceptibility factors in the etiology of infant leukemia. Blood. 1998;92:391a. 44. Petridou E, Trichopoulos D, Dessypris N, et al. Infant leukaemia after in utero exposure to radiation from Chernobyl. Nature. 1996;382:352-353. 45. Parkin DM, Clayton D, Black RJ, et al. Childhood leukaemia in Europe after Chernobyl: 5 year follow-up. Br J Cancer. 1996;73:1006-1012. 46. Michaelis J, Kaletsch U, Burkart W, Grosche B. Infant leukemia after Chernobyl accident. Nature. 1997;387:246. 47. Ziemin-van der Poel S, McCabe N, Gill HJ, et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemia. Proc Natl Acad Sci U S A. 1991;88:10735-10739. 48. Cimino G, Moir DT, Canaani O, et al. Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19) (q23;p13) chromosome translocations. Cancer Res. 1991;51:6712-6739. 49. Gu Y, Nakamura T, Alder H, et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell. 1992;71:701-708. 50. Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992;71:691-700. 51. Djabali M, Selleri L, Parry P, Bower M, Young BD, Evans GA. A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias. Nat Genet. 1993;4:431. 52. Cimino G, Nakamura T, Gu Y, et al. An altered 11-kb transcript in leukemic cell lines with t(4;11) (q21;q23) chromosome translocation. Cancer Res. 1992;52:3811-3813. 53. Rasio D, Schichman SA, Negrini M, Canaani E, Croce CM. Complete exon structure of the ALL1 gene. Cancer Res. 1996;56:1766-1769. 54. Nilson I, Löchner NK, Siegler G, et al. Exon/intron structure of the human ALL1(MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias. Br J Haematol. 1996;93:966-972. 55. Ingham PW. Genetic control of the spatial pattern of selector gene expression in Drosophila. Cold Spring Harb Symp Quant Biol. 1986;50:201-208. 56. Wedeen C, Harding K, Levine M. Spatial regulation of Antennapoedia and bithorax gene expression of the Polycomb locus in Drosophila. Cell. 1986;44:739-748. 57. Yu BD, Hess JL, Horning SE, Brown GA, Korsmeyer SJ. Altered Hox expression and segmental identity in Mll-mutant mice. Nature. 1995;378:505-508. 58. Akasaka T, Kanno M, Balling R, Mieza MA, Taniguchi M, Koseki H. A role for mel-18, a Polycomb group-related vertebrate gene, during the anteroposterior specification of the axial skeleton. Development. 1996;134:1513-1522 59. Core N, Bel S, Gaunt SJ, et al. Altered cellular proliferation in polycomb-M33-deficient mice. Development. 1997;124:721-729. 60. Yu BD, Hanson RD, Hess JL, Horning SE, Korsmeyer SJ. MLL, a mammalian trithorax-group gene, functions as a transcriptional maintenance factor in morphogenesis. Proc Natl Acad Sci U S A. 1998;95:10632-10636. 61. Nakamura T, Alder H, Gu Y, et al. Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Proc Natl Acad Sci U S A. 1993;90:4631-4635. 62. Morissey J, Tkachuck DC, Milatovich A, Francke U, Link M, Cleary ML. A serine-proline rich protein is fused to HRX in t(4;11) acute leukemias. Blood. 1993;81:1124-1131. 63. Prasad R, Gu Y, Alder H, et al. Cloning of the ALL1 fusion partner, the AF6 gene, involved in acute leukemias with t(6;11) chromosome translocation. Cancer Res. 1993;53:5624-5628. 64. Rubnitz JE, Morissey J, Savage PA, Cleary ML. ENL, the gene fused with HRX in t(11;19) leukemias, encodes a nuclear protein with transcriptional activation potential in lymphoid and myeloid cells. Blood. 1994;84:1747-1752. 65. Thirman MJ, Levitan DA, Kobayashi L, Simon MC, Rowley J. Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23;p13.1) in acute myeloid leukemia. Proc Natl Acad Sci U S A. 1994;91:12110-12114. 66. Prasad R, Leshkowitz D, Gu Y, et al. Leucine zipper dimerization motif encoded by the AF17 gene fused to ALL-1 (MLL) in acute leukemia. Proc Natl Acad Sci U S A. 1994;91:8107-8111. 67. Corral J, Forster A, Thompson S, et al. Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation. Proc Natl Acad Sci U S A. 1993;90:8538-8542. 68. Parry P, Wei Y, Evans G. Cloning and characterization of the t(X;11) breakpoint from a leukemic cell line identify a new member of the forkhead gene family. Genes Chromosomes Cancer. 1994;11:79-84. 69. Tse W, Zhu W, Chen HS, Cohen A. A novel gene, AF1q fused to MLL in t(1;11)(q21;q23), is specifically expressed in leukemic and immature hematopoietic cells. Blood. 1995;85:650-656. 70. Bernard OA, Mauchauffe M, Mecucci C, Van den Berghe H, Berger R. A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-1, AF-9 nor ENL. Oncogene. 1994;9:1039-1045. 71. Taki T, Sako M, Tsuchida M, Hayashi Y. The t(11;16)(q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene. Blood. 1997;89:3945-3950. 72. Chaplin T, Ayton P, Bernard OA, et al. A novel class of zinc finger-leucine zipper genes identified from the molecular cloning of the t(10;11) translocation in acute leukemia. Blood. 1995;85:1435-1441. 73. So CW, Caldas C, Liu MM, et al. EEN encodes for a member of a new family of proteins containing an Src homology 3 domain and is the third gene located on chromosome 19p13 that fuses to MLL in human leukemia. Proc Natl Acad Sci U S A. 1997;94:2563-2568. 74. Megonigal M, Rappaport EF, Jones DH, et al. t(11;22)(q23;q11.2) in acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes. Proc Natl Acad Sci U S A. 1998;95:6413-6418. 75. Taki T, Shibuya N, Taniwaki M, et al. ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23). Blood. 1998;92:1125-1130. 76. Osaka M, Rowley JD, Zeleznik-Le NJ. MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25). Proc Natl Acad Sci U S A. 1999;96:6428-6433. 77. Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA. AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Blood. 1997;90:3714-3719. 78. Schichman SA, Caligiuri MA, Strout MP, et al. ALL-1 tandem duplication in acute myeloid leukemia with normal karyotype involves homologous recombinations between Alu elements. Cancer Res. 1994;54:4277-4280. 79. Shichman SA, Caligiuri MA, Gu Y, et al. ALL-1 partial duplication in acute myeloid leukemia. Proc Natl Acad Sci U S A. 1994;91:6236-6239. 80. Löchner K, Siegler G, Führer M, et al. A specific deletion in the breakpoint cluster region of the ALL-1 gene is associated with acute lymphoblastic T-cell leukemias. Cancer Res. 1996;56:2171-2177. 81. Slany RK, Lavau C, Cleary ML. The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX. Mol Cell Biol. 1998;18:122-129. 82. Corral J, Lavenir I, Impey H, et al. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell. 1996;85:853-861. 83. Cui X, De Vivo I, Slany R, Miyamoto A, Firestein R, Cleary ML. Association of SET domain and myotubularin-related proteins modulates growth control. Nat Genet. 1998;18:331-337. 84. Rozenblatt-Rosen O, Rozovskaia T, Bukarov D, et al. The C-terminal SET domains of ALL1 and TRITHORAX interact with the INI1 and SNR1 proteins, components of the SWI/SNF complex. Proc Natl Acad Sci U S A. 1998;95:4152-4157. 85. Arakawa H, Nakamura T, Zhadanov AB, et al. Identification and characterization of the ARP1 gene, a target for the human acute leukemia ALL1 gene. Proc Natl Acad Sci U S A. 1998;95:4573-4578. 86. Adler HT, Chinery R, Wu DY, et al. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Mol Cell Biol. 1999;19:7050-7060. 87. Hess JL, Yu BD, Li B, Hanson R, Korsmeyer JS. Defects in yolk sac hematopoiesis in MLL-null embryos. Blood. 1997;90:1799-1806. 88. Cimino G, Lo Coco F, Biondi A, et al. ALL-1 gene at chromosome 11q23 is consistently altered in acute leukemia of early infancy. Blood. 1993;82:544-546. 89. Bower M, Parry P, Carter M, et al. Prevalence and clinical correlations of MLL gene rearrangements in AML-M4/5. Blood. 1994;84:3776-3780. 90. Cimino G, Rapanotti MC, Elia L, et al. ALL-1 gene rearrangements in acute myeloid leukemia: association with M4-M5 French-American-British classification subtypes and young age. Cancer Res. 1995;55:1625-1628. 91. Poirel H, Rack K, Delabesse E, et al. Incidence and characterization of MLL gene (11q23) rearrangements in acute myeloid leukemia M1 and M5. Blood. 1996;87:2496-2505. 92. Felix CA, Lange BJ, Hosler MR, Fertala J, Bjornsti MA. Chromosome band 11q23 translocation breakpoints are DNA topoisomerase II cleavage sites. Cancer Res. 1995;55:4287-4292. 93. Broeker PL, Super HG, Thirman MJ, et al. Distribution of 11q23 breakpoints within the MLL breakpoint cluster region in de novo acute leukemia and in treatment-related acute myeloid leukemia: correlation with scaffold attachment regions and topoisomerase II consensus binding sites. Blood. 1996;87:1912-1922. 94. Gu Y, Cimino G, Alder H, et al. The t(4;11)(q21;q23) chromosome translocations in acute leukemias involve the VDJ recombinase. Proc Natl Acad Sci U S A. 1992;89:10464-10468. 95. Gu Y, Alder H, Nakamura T, et al. Sequence analysis of the breakpoint cluster region in the ALL-1 gene involved in acute leukemia. Cancer Res. 1994;54:2326-2330. 96. Ross JA, Davies SM, Potter JD, Robison LL. Epidemiology of childhood leukemia with a focus on infants. Epidemiol Rev. 1994;16:243-272. 97. Buckley JD, Robison LL, Swotinsky R, et al. Occupational exposures of parents of children with acute nonlymphocytic leukemia: a report from the Childrens Cancer Study Group. Cancer Res. 1989;49:4030-4037. 98. Aplan PD, Chervinsky DS, Stanulla M, Burhans WC. Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors. Blood. 1996;87:2649-2658. 99. Gillert E, Leis T, Repp R, et al. A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells. Oncogene. 1999;18:4663-4671. 100. Cimino G, Rapanotti MC, Biondi A, et al. Infant acute leukemias show the same biased distribution of ALL1 gene breaks as topoisomerase II related secondary acute leukemias. Cancer Res. 1997;57:2879-2883. 101. Reaman G, Zeltzer P, Bleyer A, et al. Acute lymphoblastic leukemia in infants less than one year of age: a cumulative experience of the Children's Cancer Study Group. J Clin Oncol. 1985;3:1513-1521. 102. Chessells JM, Eden OB, Bailey CC, Lilleyman JS, Richards SM. Acute lymphoblastic leukaemia in infancy: experience in MRC UKALL trials report from the Medical Research Council Working Party on Childhood Leukaemia. Leukemia. 1994;8:1275-1279. 103. Alvarado CS, Austin GE, Borowitz MJ, et al. Myeloperoxidase gene expression in infant leukemia: a Pediatric Oncology Group Study. Leuk Lymphoma. 1998;29:145-160. 104. Hu M, Krause D, Greaves M, et al. Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev. 1997;11:774-785. 105. Basso G, Rondelli R, Covezzoli A, Putti MC. The role of immunophenotype in acute lymphoblastic leukemia of infant age. Leuk Lymphoma. 1994;15:51-60. 106. Ferster A, Bertrand Y, Benoit Y, et al. Improved survival for acute lymphoblastic leukaemia in infancy: the experience of EORTC-Childhood Leukaemia Cooperative Group. Br J Haematol. 1994;86:284-290. 107. Heerema NA, Arthur DC, Sather H, et al. Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: impact of the 11q23 breakpoint on outcome: a report of the Childrens Cancer Group. Blood. 1994;83:2274-2284. 108. Reiter A, Schrappe M, Ludwig WD, et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood. 1994;84:3122-3133. 109. Cimino G, Rapanotti MC, Rivolta A, et al. Prognostic relevance of ALL-1 gene rearrangement in infant leukemias. Leukemia. 1995;9:391-395. 110. Hilden JM, Frestedt JL, Moore RO, et al. Molecular analysis of infant acute lymphoblastic leukemia: MLL rearrangement and reverse transcriptase-polymerase chain reaction for t(4;11)(q21;q23). Blood. 1995;86:3876-3882. 111. Pui CH, Ribeiro RC, Campana D, et al. Prognostic factors in the acute lymphoid and myeloid leukemias of infants. Leukemia. 1996;10:952-956. 112. Reaman GH, Sposto R, Sensel MG, et al. Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. J Clin Oncol. 1999;17:445-455. 113. Basso G, Putti MC, Cantu-Rajnoldi A, et al. The immunophenotype in infant acute lymphoblastic leukaemia: correlation with clinical outcome. an Italian multicentre study (AIEOP). Br J Haematol. 1992;81:184-191. 114. Pui CH, Behm FG, Downing JR, et al. 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. J Clin Oncol. 1994;12:909-915. 115. Rubnitz JE, Link MP, Shuster JJ, et al. Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1994;2:570-573. 116. Chen CS, Sorensen PHB, Domer PH, et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood. 1993;81:2386-2393. 117. Taki T, Ida K, Bessho F, et al. Frequency and clinical significance of the MLL gene rearrangements in infant acute leukemia. Leukemia. 1996;10:1303-1307. 118. Heerema NA, Sather HN, Ge J, et al. Cytogenetic studies of infant acute lymphoblastic leukemia: poor prognosis of infants with t(4;11): a report of the Children's Cancer Group. Leukemia. 1999;13:679-686. 119. Rubnitz JE, Camitta BM, Mahmoud H, et al. Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19) (q23;p13.3) translocation. J Clin Oncol. 1999;17:191-196. 120. Pui CH, Frankel LS, Carroll AJ, et al. Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11) (q21;q23): a collaborative study of 40 cases. Blood. 1991;77:440-447. 121. Johansson B, Moorman AV, Haas OA, et al. Haematologic malignancies with t(4;11)(q21;q23): a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. Leukemia. 1998;12:779-787. 122. Dördelmann M, Reiter A, Borkhardt A, et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood. 1999;94:1209-1217. 123. Vormoor J, Ritter J, Creutzig U, et al. Acute myelogenous leukaemia in children under 2 years: experiences of the West German AML studies BFM-78, -83 and -87. AML-BFM Study Group. Br J Cancer Suppl. 1992;S63-S67. 124. Satake N, Maseki N, Nishiyama M, et al. Chromosome abnormalities and MLL rearrangement in acute myeloid leukemia of infants. Leukemia. 1999;13:1013-1017. 125. Sorensen PH, Chen CS, Smith FO, et al. Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. J Clin Invest. 1994;93:429-437. 126. Lie SO, Jonmundsson G, Mellander L, Siimes MA, Yssing M, Gustafsson G. A population-based study of 272 children with acute myeloid leukaemia treated on two consecutive protocols with different intensity: best outcome in girls, infants, and children with Down's syndrome. Nordic Society of Paediatric Haematology and Oncology (NOPHO). Br J Haematol. 1996;94:82-88. 127. Grier HE, Gelber RD, Camitta BM, et al. Prognostic factors in childhood acute myelogenous leukemia. J Clin Oncol. 1987;5:1026-1032. 128. Pui C-H, Raimondi SC, Srivastava DK, et al. Prognostic factors in infants with acute myeloid leukemia. Leukemia. 2000;14:684-687. 129. Kumagai M, Manabe A, Pui CH, et al. Stroma-supported culture in childhood B-lineage acute lymphoblastic leukemia cells predicts treatment outcome. J Clin Invest. 1996;97:755-760. 130. Uckun FM, Sather H, Reaman G, et al. Leukemic cell growth in SCID mice as a predictor of relapse in high-risk B-lineage acute lymphoblastic leukemia. Blood. 1995;85:873-878. 131. Kersey JH, Wang D, Oberto M. Resistance of t(4;11) (MLL-AF4 fusion gene) leukemias to stress-induced cell death: possible mechanism for extensive extramedullary accumulation of cells and poor prognosis. Leukemia. 1998;12:1561-1564. 132. Pieters R, den Boer ML, Durian M, et al. Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia: implications for treatment of infants. Leukemia. 1998;12:1344-1348. 133. Pieters R, Huismans DR, Loonen AH, et al. Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukemia. Lancet. 1991;338:399-403. 134. Kaspers GJ, Veerman AJ, Pieters R, et al. In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia. Blood. 1997;90:2723-2729. 135. Hongo T, Yajima S, Sakurai M, Horiloshi Y, Hanada R. In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia. Blood. 1997;89:2959-2965. 136. Silverman LB, McLean TW, Gelber RD, et al. Intensified therapy for infants with acute lymphoblastic leukemia (ALL): results from the Dana-Farber Cancer Institute Consortium. Cancer. 1997;80:2285-2295. 137. Ludwig WD, Rieder H, Bartram CR, et al. Immunophenotypic and genotypic features, clinical characteristics, and treatment outcome of adult pro-B acute lymphoblastic leukemia: results of the German Multicenter trials GMALL 03/87 and 04/89. Blood. 1998;92:1898-1909. 138. Friis-Hansen B. Body composition during growth: in vivo measurements and biochemical data correlated to differential anatomical growth. Pediatrics. 1971(suppl 2);47:264. 139. Stewart CF, Hampton EM. Effect of maturation on drug disposition in pediatric patients. Clin Pharm. 1987;6:548-564. 140. Pelkonen O, Kaltiala EH, Larmi TKI, Karki N. Comparison of activities of drug-metabolizing enzymes in human fetal and adult livers. Clin Pharmacol Ther. 1973;14:840-846. 141. Aranda JV, Macleod SM, Renton KE, Eade NR. Hepatic microsomeal drug oxidation and electron transport in newborn infants. J Pediatr. 1974;85:534-542. 142. Siegel SE, Moran RG. Problems in the chemotherapy of cancer in the neonate. Am J Pediatr Hematol Oncol. 1981;3:287-296. 143. Milsap RL, Jusko WJ. Pharmacokinetics in the infant. Environ Health Perspect. 1994;102:107-110. 144. Bleyer WA. Clinical pharmacology of intrathecal methotrexate, II: an improved dosage regimen derived from age-related pharmacokinetics. Cancer Treat Rep. 1977;61:1419-1425. 145. McLeod HL, Relling MV, Crom WR, et al. Disposition of antineoplastic agents in the very young child. Br J Cancer Suppl. 1992;66:S23-S29. 146. Allen JC. The effects of cancer therapy on the nervous system. J Pediatr. 1978;93:903-909. 147. Woods WG, O'Leary M, Nesbit ME. Life-threatening neuropathy and hepatotoxicity in infants during induction therapy for acute lymphoblastic leukemia. J Pediatr. 1981;98:642-645. 148. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998;339:605-615. 149. Ishii E, Okamura J, Tsuchida M, et al. Infant leukemia in Japan: clinical and biological analysis of 48 cases. Med Pediatr Oncol. 1991;19:28-32. 150. Reaman GH, Steinherz PG, Gaynon PS, et al. Improved survival of infants less than 1 year of age with acute lymphoblastic leukemia treated with intensive multiagent chemotherapy. Cancer Treat Rep. 1987;71:1033-1038. 151. Lauer SJ, Camitta BM, Leventhal BG, et al. Intensive alternating drug pairs after remission induction for treatment of infants with acute lymphoblastic leukemia: a Pediatric Oncology Group pilot study. J Pediatr Hematol Oncol. 1998;20:229-233. 152. Frankel LS, Ochs J, Shuster JJ, et al. Therapeutic trial for infant acute lymphoblastic leukemia: the Pediatric Oncology Group experience (POG 8493). J Pediatr Hematol Oncol. 1997;19:35-42. 153. Dreyer ZE, Steuber CP, Bowman WP, et al. High risk infant ALL and improved survival with intensive chemotherapy. Proc Am Soc Clin Oncol. 1998;17:529a. 154. Rivera GK, Raimondi SC, Hancock ML, et al. Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet. 1991;337:61-66. 155. Kaleita TA, Reaman GH, MacLean WE, Sather HN, Whitt JK. Neurodevelopmental outcome of infants with acute lymphoblastic leukemia: a Children's Cancer Group report. Cancer. 1999;85:1859-1865. 156. Pui CH, Evans WE. Acute lymphoblastic leukemia in infants. J Clin Oncol. 1999;17:438-440. 157. Grier HE, Gelber RD, Camitta BM, et al. Prognostic factors in childhood acute myelogenous leukemia. J Clin Oncol. 1987;5:1026-1032. 158. Amadori S, Ceci A, Comelli A, et al. Treatment of acute myelogenous leukemia in children: results of the Italian Cooperative Study AIEOP/LAM 8204. J Clin Oncol. 1987;5:1356-1363. 159. Pui CH, Kalwinsky DK, Schell MJ, Mason CA, Mirro J Jr, Dahl GV. Acute nonlymphoblastic leukemia in infants: clinical presentation and outcome. J Clin Oncol. 1988;6:1008-1013. 160. Buckley JD, Chard RL, Baehner RL, et al. Improvement in outcome for children with acute nonlymphocytic leukemia: a report from the Childrens Cancer Study Group. Cancer. 1989;63:1457-1465. 161. Ravindranath Y, Steuber CP, Krischer J, et al. High-dose cytarabine for intensification of early therapy of childhood acute myeloid leukemia: a Pediatric Oncology Group study. J Clin Oncol. 1991;9:572-580. 162. Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996;334:1428-1434. 163. Béhar C, Suciu S, Benoit Y, et al. Mitoxantrone-containing regimen for treatment of childhood acute leukemia (AML) and analysis of prognostic factors: results of the EORTC Children Leukemia Cooperative Study 58872. Med Pediatr Oncol. 1996;26:173-179. 164. Woods WG, Kobrinsky N, Buckley JD, et al. Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood. 1996;87:4979-4989. 165. Stevens RF, Hann IM, Wheatley K, Gray RG. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukaemia: results of the United Kingdom Medical Research Council's 10th AML trial. Br J Haematol. 1998;101:130-140. 166. Creutzig U, Zimmermann M, Ritter J, et al. Definition of a standard-risk group in children with AML. Br J Haematol. 1999;104:630-639. 167. Wells RJ, Woods WG, Buckley JD, et al. Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study. J Clin Oncol. 1994;12:2367-2377. 168. Odom LF, Gordon EM. Acute monoblastic leukemia in infancy and early childhood: successful treatment with an epipodophyllotoxin. Blood. 1984;64:875-882. 169. Nishikawa A, Nakamura Y, Nobori U, et al. Acute monocytic leukemia in children: response to VP-16-213 as a single agent. Cancer. 1987;60:2146-2149. 170. Carroll A, Civin C, Schneider N, et al. The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group study. Blood. 1991;78:748-752. 171. Lion T, Haas OA, Harbott J, et al. The translocation t(1;22) (p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children. Blood. 1992;79:3325-3330. 172. Johnson FL, Sanders JE, Ruggiero M, Chard RL Jr, Thomas ED. 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