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Blood, 17 September 2009, Vol. 114, No. 12, pp. 2365-2366. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Lange, B. J. PubMed PubMed Citation Articles by Lange, B. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Comment on Balgobind et al, page 2489 T(11q23): brand necessary Beverly J. Lange CHILDREN'S HOSPITAL OF PHILADELPHIA A large intergroup investigation of MLL translocation partners in pediatric AML discovers low-risk star, t(1;11), confirms high-risk chromosomes 6 and 10 partners, and declares generic t11q23 insufficient for risk stratification.1 Risk-stratification of disease is a cornerstone of leukemia therapy. Rearrangements of the MLL gene on chromosomal band 11q23 are considered high-risk. Within MLL-rearranged leukemia, age, phenotype, translocation partner, and additional chromosomal aberrations are prognostic indicators in some studies. To examine how MLL translocation partners and these other variables correlate with prognosis in pediatric acute myeloid leukemia (AML), in this issue of Blood, Balgobind and colleagues review outcomes of 756 children with confirmed MLL-rearranged AML treated on recent clinical trials of 11 collaborative groups from 15 countries.1 The 5-year event-free survival (EFS) is 44%1 and overall survival (OS) 56% in the MLL-rearranged cohort, the same as the respective medians for all AML treated after 1992 in these collaborative groups.1 Thus, generic MLL rearrangement appears to be an intermediate-risk type of pediatric AML. Outcomes within the MLL- rearranged cohort vary significantly according to translocation partner ranging from 11% EFS in t(6;11)(q27;q23) rearrangement to 92% EFS in t(1:11)(q21;p23) rearrangement (see figure).1 In rearranged t(9;11) AML, EFS is 50%, that is, intermediate, although within the t(9;11) subset FAB M5 is a relatively favorable phenotype.1 Older age, additional cytogenetic aberrations, and leukocyte count more than 100 x 109/L are unfavorable. The 5-year OS of 100% in the 3% of children with t(1:11)(q21;p23) is remarkable. The 1q21 partner gene, AF1q, encodes a proapototic mitochondrial membrane protein expressed in normal hematopoietic progenitors and variably expressed in AML and other cancers.2 In vitro AF1q overexpression confers resistance to doxorubicin,3 and overexpression is associated with poor prognosis in pediatric AML.4 The der MLL fusion partner forms an oncogenic protein; the der AF1q partner forms no protein.3 Comparison of the activity of der MLL fusion protein in t(1:11)(q21;p23) with those of less favorable translocations may explain their different sensitivities to therapy. The heterogeneity of outcomes within MLL-rearranged AML implies that generic classification of AML as t(11q23) is no longer sufficient for risk stratification. However, for partner identification to become standard practice, it must be accomplished expeditiously and economically. The Balgobind study uses a combination of cytogenetics and complementary FISH and molecular techniques to identify all translocation partners; expert review is retrospective.1 An equally large collaborative investigation reported by Meyer et al uses long-distance PCR to characterize 384 pediatric and 376 adult cases of the MLL-rearranged AML or ALL.5 This method identifies all reciprocal MLL fusions and structural abnormalities and provides patient-specific PCR probes for monitoring minimal residual disease.5 If the Meyer study is validated in real time, long-distance PCR could become standard for MLL partner identification. Event-free survival curves for patients with 11q23/MLL-rearranged pediatric AML grouped on the basis of different translocation partners. Assignment to 11q23-rearranged subgroups was based on translocation partners, as identified after central review of karyotyping. Some patients were assigned to 11q23 subgroups based on RT-PCR results only. If an MLL rearrangement was determined by FISH and the translocation partner was unkown, the patient was included in the "11q23/MLL-other" group. At least 10 patients had to be included to create a subgroup, otherwise the cases were allocated to the 11q23/MLL-other group. Patients with a t(1;11)(q21;q23) showed independent favorable outcome with overall survival at 5 years of 100% (± 0%) and an event-free survival of 92% (± 5%). Several rearrangements were identified as predictors of poor clinical outcome, including t(6;11)(q27;q23), t(10;11)(p11.2;q23), t(4;11)(q21;q23), and t(10;11)(p12;q23). See the complete figure in the article beginning on page 2489. The purpose of risk stratification is to assign treatment according to risk of relapse or death. Probably children with t(1:11)(q21;p23) rearrangement need less treatment while those with the other rearrangements need better treatment. Unlike MLL-rearranged leukemia in adults,6 allogeneic stem cell transplantation is no better than chemotherapy in children.1 Better therapy is likely to involve agents that impair targets normally controlled by MLL such as clustered HOX homeobox genes or novel enzymatic activities of fusion proteins.7,8 Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114(12):2489–2496.[Abstract/Free Full Text] 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(3):650–656.[Abstract/Free Full Text] Co NN, Tsang WP, Wong TW, et al. Oncogene AF1q enhances doxorubicin-induced apoptosis through BAD-mediated mitochondrial apoptotic pathway. Mol Cancer Ther. 2008;7(10):3160–3168.[Abstract/Free Full Text] Tse W, Meshinchi S, Alonzo TA, et al. Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia. Blood. 2004;104(10):3058–3063.[Abstract/Free Full Text] Meyer C, Kowarz E, Hofmann J, et al. New insights to the MLL recombinome of acute leukemias. Leukemia. 2009;23(8):1440–1499. Krauter J, Wagner K, Schfer I, et al. Prognostic factors in adult patients up to 60 years old with acute myeloid leukemia and translocations of chromosome band 11q23: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2009;27(18):3000–3006.[Abstract/Free Full Text] Slany RK. The molecular biology of mixed lineage leukemia. Haematologica. 2009;94(7):984–993.[Abstract/Free Full Text] Bennett CA, Winters AC, Barretto NN, Hemenway CS. Molecular targeting of MLL-rearranged leukemia cell lines with the synthetic peptide PFWT synergistically enhances the cytotoxic effect of established chemotherapeutic agents. Leuk Res. 2009;33(7):937–947.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study Brian V. Balgobind, Susana C. Raimondi, Jochen Harbott, Martin Zimmermann, Todd A. Alonzo, Anne Auvrignon, H. Berna Beverloo, Myron Chang, Ursula Creutzig, Michael N. Dworzak, Erik Forestier, Brenda Gibson, Henrik Hasle, Christine J. Harrison, Nyla A. Heerema, Gertjan J. L. Kaspers, Anna Leszl, Nathalia Litvinko, Luca Lo Nigro, Akira Morimoto, Christine Perot, Rob Pieters, Dirk Reinhardt, Jeffrey E. Rubnitz, Franklin O. Smith, Jan Stary, Irina Stasevich, Sabine Strehl, Takashi Taga, Daisuke Tomizawa, David Webb, Zuzana Zemanova, C. Michel Zwaan, and Marry M. van den Heuvel-Eibrink Blood 2009 114: 2489-2496. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Lange, B. J. PubMed PubMed Citation Articles by Lange, B. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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