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NEOPLASIA
From the Fred Hutchinson Cancer Research Center,
Seattle, Washington.
The prevalence and significance of genetic abnormalities in older
patients with acute myeloid leukemia (AML) are unknown. Polymerase
chain reactions and single-stranded conformational polymorphism
analyses were used to examine 140 elderly AML patients enrolled in the
Southwest Oncology Group study 9031 for FLT3, RAS, and TP53 mutations,
which were found in 34%, 19%, and 9% of patients,
respectively. All but one of the FLT3 (46 of 47) mutations
were internal tandem duplications (ITDs) within exons 11 and 12. In the
remaining case, a novel internal tandem triplication was found in exon
11. FLT3 ITDs were associated with higher white blood cell
counts, higher peripheral blast percentages, normal cytogenetics, and
less disease resistance. All RAS mutations (28 of 28) were
missense point mutations in codons 12, 13, or 61. RAS
mutations were associated with lower peripheral blast and bone marrow
blast percentages. Only 2 of 47 patients with FLT3 ITDs
also had a RAS mutation, indicating a significant negative association between FLT3 and RAS mutations
(P = .0013). Most TP53 mutations (11 of 12)
were missense point mutations in exons 5 to 8 and were associated with
abnormal cytogenetics, especially abnormalities in both chromosomes 5 and 7. FLT3 and RAS mutations were not
associated with inferior clinical outcomes, but TP53 mutations were associated with a worse overall survival (median 1 versus 8 months, P = .0007). These results indicate that
mutations in FLT3, RAS, or TP53 are
common in older patients with AML and are associated with specific AML
phenotypes as defined by laboratory values, cytogenetics, and clinical outcomes.
(Blood. 2001;97:3589-3595) The incidence of acute myeloid leukemia (AML) rises
dramatically with age,1 yet treatment of elderly AML
patients ( RAS, FLT3, and TP53 genes play
important roles in the regulatory processes that govern proliferation,
differentiation, and apoptosis,8-12 and abnormalities in
these 3 genes have been implicated in the pathogenesis of younger adult
patients with AML. Point mutations in RAS oncogenes occur in
approximately 20% of de novo AML patients.13-15 The
prognostic significance of RAS mutations remains unknown,
with most large studies finding no clinical
significance.14,16 Recently, studies have reported that
approximately 20% of younger adult patients with AML have internal
tandem duplications (ITDs) within the FLT3 gene, a subclass
III tyrosine kinase receptor,17-24 and Kiyoi and coworkers
found that the presence of an FLT3 ITD was the strongest
predictor for an inferior survival in adult AML patients under the age
of 60 years.21 Studies have also found TP53
mutations in up to 15% of adult patients with AML,25-28 and Wattel and colleagues demonstrated that TP53 mutations
were associated with older age and a reduced overall
survival.28
Few studies have examined the genetic abnormalities in older patients
with AML, and none has examined multiple oncogenes and tumor suppressor
genes in a single cohort of elderly patients with AML. Because
RAS, FLT3, and TP53 have important
interactions, examining these genes in the same cohort of patients may
provide information about patterns of genetic disruption in AML.
Therefore, we evaluated FLT3, RAS, and
TP53 mutations in 140 older patients with AML enrolled in
Southwest Oncology Group (SWOG) study 9031.
Patients and samples
Polymerase chain reaction of NRAS,
KRAS, FLT3, and
TP53 fragments
Single-strand conformation polymorphisms Single-strand conformation polymorphism (SSCP) analyses were performed to detect mutations as previously described.31,33,34 All gels were stained with SYBR green II RNA stain (Molecular Probes, Eugene, OR) at least 45 minutes without prewashing or destaining. Gels were examined for single-strand DNA (ssDNA) shifts on an Eagle Eye II (Stratagene, La Jolla, CA).Direct nucleotide sequencing of the amplified fragments The SSCP bands were cut from gels, and ssDNA was extracted with diethyl pyrocarbonate (DEPC) water.31 The ssDNA was reamplified to generate a sequencing template using the conditions described for the PCR methods. The amplified product was electrophoresed through a 2% agarose gel. The double-strand DNA (dsDNA) PCR product was extracted and sequenced as previously described.31 In the case of the FLT3 gene, reamplified PCR product was also electrophoresed through a 5% polyacrylamide gel. High-molecular-weight bands were excised, and dsDNA was extracted with DEPC water. The dsDNA then was directly sequenced using the Thermo Sequence Dye Terminator Sequencing Reaction.31Statistical methods Clinical, demographic, cytogenetic, and outcome data for patients in this study were collected and evaluated using standard SWOG procedures. The crude prevalence of one or more mutations in a group of patients was defined by expressing as a percentage the number of patients (Mi) bearing the mutation(s) among those who were genotyped (Ni), that is, Pi = (Mi/Ni) × 100%, where i is an index of patient groups. The selection of genotyped patients was known to be biased in favor of those with high white blood cell (WBC) counts, which might be associated with mutation prevalence. Therefore, adjusted prevalence estimates were calculated as the weighted average P* = (wi × Pi), where wi
is the proportion of all patients in study SWOG 9031 in the
i-th WBC category. The WBC categories were defined arbitrarily
by cut-points at 5000, 20 000, 50 000, and 100 000 cells/µL. The
strength of association between mutations in pairs of genes
was represented by the cross-product ratio,
CPR = (Mpp × Maa)/(Mpa × Map),
where Mij is the number of patients with mutation present
(p) or absent (a) in the first (i) or second (j) gene. CPR = 1
indicates the absence of association, and CPR approaches 0 for
increasingly strong negative associations. Complete response (CR) and
resistant disease (RD) were defined as in the original clinical
trial.29 Overall survival (OS) was measured from the date
of entry into the trial until death from any cause, with observation
censored for patients last known to be alive. For patients achieving
CR, relapse-free survival (RFS) was measured from the date CR was
established until AML relapse or death from any cause, with observation
censored for patients last known to be alive without report of relapse.
The Fisher exact test, Pearson chi-square test for independence,
Wilcoxon and Kruskal-Wallis tests, and the log-rank test were used to
test the heterogeneity of variables among groups defined by the
presence of mutations. Logistic regression models were used to examine
associations of mutation frequencies with patient characteristics and
the prognostic effects of mutations and other factors on CR and RD.
Proportional hazards regression models were used to examine the
prognostic effects of mutations and other factors on OS and RFS.
Statistical significance was reported in terms of 2-tailed P
values, and confidence intervals (CIs) were all calculated at the
95% confidence level. The analysis was based on data available as of
December 16, 1999.
Primary analyses of RAS, FLT3, and TP53 mutations Characteristics of the study population.
Pretreatment specimens were available for 140 of the 234 elderly
patients in study SWOG 9031. Genotyped patients had higher peripheral
blast counts, higher percentages of marrow blasts, higher WBC counts,
lower CD34+ blast percentages, different distribution of
French-American-British (FAB) classification, higher proportions of
normal cytogenetic samples, and lower proportions of unfavorable
cytogenetic samples, compared to the 94 patients unavailable for
evaluation (Table 2). No significant
differences between the genotyped and unavailable patients were found
with respect to age, sex, race, MDR1 status, CR, RD, RFS, or
OS.
Characteristics, frequency, and clinical significance of
RAS mutations.
We found 28 RAS mutations in the 140 genotyped patients
(Figure 1A). A total of 26 patients
(19%, CI 13%-26%) had a mutation in either NRAS
or KRAS, with 2 patients (1%) having mutations in both
NRAS and KRAS. Accounting for the elevated WBC
counts of the genotyped patients, the adjusted estimate for
RAS mutations was 16%. The mutational frequencies for
individual codons were as follows: NRAS codon 12 (7%, 10 of
140); NRAS codon 13 (2%, 3 of 140); NRAS codon
61 (3%, 4 of 140); KRAS codon 12 (5%, 7 of 140);
KRAS codon 13 (2%, 3 of 140); and KRAS
codon 61 (1%, 1 of 140). All RAS mutations were missense
point mutations, changing the wild-type amino acid to a different amino
acid. Overall, a glycine to aspartic acid (G
Primary analyses revealed that patients with a RAS mutation had significantly lower percentages of peripheral (8% versus 43%, P = .004) and marrow blasts (61% versus 71%, P = .03) compared to those without a RAS mutation. However, no significant differences were found between the 2 groups with respect to cytogenetics, age, WBC counts, CD34+ blast percentage, or clinical outcomes (Table 3).
Characteristics, frequency, and clinical significance of
FLT3 mutations.
The FLT3 ITDs were detected in 41 of 140 (29%, CI
22%-38%) samples using agarose electrophoresis of PCR product (Figure
2A). SSCP analyses found 6 additional
ITDs (Figure 2B), increasing the frequency to 47 of 140 (34%, CI
26%-42%). The 6 patients with FLT3 ITDs detected by SSCP
had lower marrow blast percentages (61% versus 78%), peripheral blast
percentages (34% versus 72%), and WBC counts (21 500 versus
62 000/µL) compared to the other 41 patients with FLT3
ITDs. The WBC-adjusted estimate of prevalence for FLT3 ITDs
was 27%. Duplications ranged in size from 24 to 141 nucleotides. Most
of the ITDs (72%) had between 3 and 15 nucleotides inserted at the
beginning of the duplication (Figure 3A).
All 47 FLT3 ITDs, including those with nucleotide
insertions, were in-frame. In addition, sample no. 8 had a previously
undescribed internal triplication (codons 603-609) (Figure 3B). All but
one of the ITDs were localized to exon 11. The remaining case involved a large duplication that started in the distal part of exon 11 and
ended in the proximal part of exon 12.
Compared to patients without FLT3 ITDs, those with FLT3 ITDs had significantly higher WBC counts (median 59.4 versus 20.3, P = .0003), higher absolute peripheral blast counts (median 26.6 versus 4.1, P = .0001), and lower percentage of CD34+ blasts (median 13% versus 65%, P = .0039). In addition, FLT3 ITDs were associated with normal cytogenetics (77% versus 40%, P = .0006) and consequently with intermediate cytogenetic risk (P = .0008). Despite the cytogenetic differences, FLT3 ITDs were not associated with significant differences in OS or RFS, although RD was slightly less frequent in the patients with FLT3 ITDs (Table 3). Characteristics, frequency, and clinical significance of TP53 mutations. We found TP53 mutations in 12 of 140 (9%, CI 5%-14%) patients, with a WBC-adjusted prevalence estimate of 10%. TP53 mutations occurred in all 4 exons studied: exon 5 (4 mutations); exon 6 (1 mutation); exon 7 (3 mutations); and exon 8 (4 mutations). Most mutations (11 of 12) were missense point mutations that resulted in a single amino acid substitution. In one case, we found a single nucleotide deletion in codon 241 of exon 7, resulting in a premature stop codon. Mutations clustered near previously reported "hot spots," particularly around codons 175 and 273, but only 2 mutations were found within these "hot spots." The missense point mutations caused a variety of amino acid substitutions, with no particular amino acid substitution predominating. The TP53 mutations were not significantly associated with WBC counts, peripheral blast counts, or blast percentages (Table 3), but were significantly associated with abnormal cytogenetics (91% versus 45%, P = .004), unfavorable cytogenetic risk (91% versus 17%, P < .0001), and worse OS (1 versus 8 months, P = .0007). Additional investigation of the 109 patients with cytogenetic data revealed that 6 (55%) of the 11 patients with TP53 mutations had abnormalities of both chromosomes 5 and 7, whereas none of the 98 patients without a TP53 mutation had abnormalities in both chromosomes 5 and 7.Secondary analyses of RAS, FLT3, and TP53 mutations Correlation between RAS, FLT3, and TP53 mutations. Approximately 50% (71 of 140) of older AML patients had mutations in FLT3 or RAS, with only 2 having mutations in both FLT3 and RAS. Consequently, the proportion of samples with a RAS mutation was significantly lower among patients with FLT3 mutations (2 of 47 or 4%) compared with those without FLT3 mutations (24 of 93 or 26%, CPR = 0.13, P = .0013). Similarly, nonsignificant negative associations of lesser magnitude were observed between TP53 mutations and mutations in either FLT3 (CPR = 0.37, P = .34) or RAS (CPR = 0.37, P = .47), as only 3 patients had a TP53 mutation and a mutation in one of the other genes. In total, 57% of the elderly AML samples harbored mutations in one or more of the RAS, FLT3, or TP53 genes. After accounting for the effect of WBC counts, the adjusted estimate of prevalence was 50%. Correlations of specific mutations with laboratory values, cytogenetics, and clinical response. We were interested in comparing the characteristics of subgroups of patients with a specific mutation to other subgroups of patients with different mutations, believing that these analyses may provide insight into the heterogeneity of AML. We, therefore, defined 3 groups based on the presence of mutations in a single gene: RAS+ (23 patients), FLT3+ (43 patients), and TP53+ (9 patients). The patients with no mutations in any of the 3 genes comprised a fourth group, designated NM, for comparison (60 patients). The 5 patients with mutations in 2 separate genes were omitted from the following analyses. There were significant heterogeneities among the 4 groups with respect to WBC counts (P = .0004), marrow blast percentage (P = .0045), peripheral blast percentage (P = .0002), absolute peripheral blast counts (P = .0003), CD34+ blast percentages (P = .0092), presence of any cytogenetic abnormality (P = .0001), and cytogenetic risk group (P < .0001). There was no significant heterogeneity with respect to age (P = .081), secondary AML (P = .72), or FAB classification (P = .48). To better elucidate the heterogeneity among the 4 groups, each mutated group was compared separately to the NM group (Table 4). All of the associations discovered in the primary analyses retained their clinical significance in these secondary analyses. In addition, previously unrecognized associations were demonstrated. For example, in the primary analysis, the presence of RAS mutations was not associated with significant differences in WBC counts or CD34+ blast percentage (Table 3). However, in the secondary analysis, patients in the RAS+ group tended to have higher WBC counts (median 34.2 versus 18.5, P = 0.08) and a significantly lower CD34+ blast percentage (median 35% versus 70%, P = .048), compared with those in the NM group. As Table 4 demonstrates, this occurred because the median CD34+ blast percentage for the RAS+ group lies between the relatively high medians of the NM and TP53+ groups and the relatively low median of the FLT3+ group.
We examined the prevalence and significance of FLT3, RAS, and TP53 mutations in 140 of 234 older patients with AML in a single SWOG trial. The genotyped group differed in several respects from the patients not included (Table 2). In particular, the genotyped patients had higher WBC and blast percentages. These differences probably reflect the fact that the genotyped patients were selected on the basis of having material available for study. Although genotyped patients had higher WBC counts, there were no significant differences between the genotyped patients and unavailable patients with respect to clinical outcomes. Fifty-seven percent of the older AML patients in our study had a mutation in FLT3, RAS, and/or TP53. This prevalence was reduced slightly to 50% after adjusting for the overrepresentation of patients with higher WBC counts. Individually, the WBC-adjusted prevalences for FLT3, RAS, and TP53 mutations were 27%, 16%, and 10%, respectively. We also demonstrated that specific mutations were associated with specific AML "phenotypes." For example, FLT3 ITDs were associated with higher WBC counts, higher blast counts, normal cytogenetics, lower percentage of CD34+ blasts, and less resistant disease. Patients with RAS mutations had higher WBC counts, lower percentage of blasts, and lower percentage of CD34+ blasts, compared to patients without a mutation in either FLT3, RAS, or TP53. Mutations of TP53 were associated with unfavorable cytogenetics and inferior OS. Finally, unlike most larger retrospective studies in adult patients with AML, FLT3 ITDs were not associated with inferior clinical outcomes in our population of older patients with AML.21,35-37 The WBC-adjusted prevalences of RAS and TP53 mutations (16% and 10%, respectively) in our cohort of older patients with AML were similar to the prevalences that have been reported in younger adults with de novo AML (15%-20% for RAS mutations and 5%-15% for TP53 mutations).13,14,21,27,28,38 However, the prevalence of FLT3 ITDs in our cohort of AML patients (WBC-adjusted prevalence, 27%) was higher than in previous reports (5%-15% in children, 15%-23% in younger adults).19,21,22,35 Taken together, the results suggest that the prevalence of FLT3 ITDs increases as the age of the AML patient increases. However, some of the increased prevalence of FLT3 ITDs in our study may have resulted from the use of the more sensitive SSCP assay. We have found that SSCP detects 0.4% to 0.8% of FLT3 ITD+ DNA in a background of DNA from a normal bone marrow, whereas agarose electrophoresis only detects 3% to 6% of FLT3 ITD+ DNA in a background of normal DNA (D.L.S., unpublished data, August 2000). In our study, SSCP identified 6 additional FLT3 ITDs, reiterating the improved sensitivity of SSCP. Why FLT3 ITDs would be present in patients with leukemia at levels below 3% to 6% is unknown. These patients had relatively lower blast counts in the marrow and peripheral blood, and thus, the improved sensitivity of SSCP may have been required to detect the FLT3 ITD. Or, perhaps, only subclones of leukemia cells harbored FLT3 ITDs. Indeed, mutations in other genes such a RAS may occur in small populations of AML cells within a given patient.16 No prior studies have evaluated a single cohort of previously untreated patients with AML for mutations in FLT3, RAS, and TP53. Nakano and coworkers examined 28 relapsed AML patients (median age, 53.5 years) who were enrolled on a variety of different treatment protocols.36 They found 23 mutations in the 28 relapsed AML patients, with 5 patients harboring more than one mutation. A total of 60% (17 of 28) of patients had at least one mutation in either FLT3, RAS, or TP53. Although many of the mutations were present in both the diagnostic and relapsed samples, 8 mutations were found exclusively at relapse, and 5 mutations were found exclusively at diagnosis. This study also analyzed the clinical significance of NRAS, FLT3, and TP53 mutations in their relapsed AML patients. They found that NRAS mutations had no impact on prognosis, whereas FLT3 and TP53 mutations were associated with a shorter overall survival.36 Other retrospective studies have also demonstrated that FLT3 ITDs are associated with inferior clinical outcomes, especially in younger AML patients and children,19,21,35,36 and a recent small subgroup analysis of 31 older patients with AML (> 60 years) found that the 7 patients with FLT3 ITDs had a worse prognosis.37 However, all these studies were composed of heterogeneous groups of AML patients who were enrolled in a variety of different treatment protocols.19,21,36,37 In our cohort of 140 older patients with AML enrolled in a single treatment trial, FLT3 ITDs were not associated with inferior clinical outcomes, but rather with less disease resistance. Several reasons could explain the differences in clinical outcomes between our study compared to previous studies. Perhaps the clinical effects of FLT3 ITDs in older patients with AML are overshadowed by the poor OS in this population. Alternatively, FLT3 ITDs in older patients may have slightly different effects due to intrinsic biologic differences in the myeloid cells of older patients. Or, FLT3 ITDs may differ between younger and older AML patients. Additional analyses comparing the sequences, location, and characteristics of FLT3 ITDs will be required to address this later possibility. Only 4% (2 of 47) of older, AML patients with FLT3 ITDs
also had a RAS mutation. If FLT3 and
RAS mutations were independent, a significantly higher
percentage of samples would harbor both FLT3 and
RAS mutations. Also, we found some phenotypic similarities between patients with FLT3 and RAS mutations.
Both groups had higher WBC counts and lower percentages of patients
with CD34+ blasts. These findings suggest that
FLT3 and RAS mutations may elicit their effects
through similar pathways, and in vitro biologic data link the
FLT3 and RAS pathways. Activation of the
FLT3 gene phosphorylates phospholipase C- Mutations in the FLT3, RAS, and TP53 genes are relatively common in elderly patients with AML, with estimated prevalences of 27%, 16%, and 10%, respectively. The prognostic significance of these mutations remains unknown, and larger, prospective analyses will be needed to clarify the clinical significance of these mutations. Also, additional genetic analyses may discover other prognostic factors that can be used to develop a more informative system of risk stratification for AML. This risk stratification will be invaluable for patient selection in future treatment protocols. Because of the high frequency of these FLT3 ITDs, these mutations may be useful for monitoring minimal residual disease in AML, and we and others are developing assays to use FLT3 ITDs for this purpose. Also, molecular investigations that interrogate the pathways of these 3 genes may illuminate critical points within these pathways that can be targeted for future treatments. Similar molecular targets have already been developed for chronic myelogenous leukemia.41
Submitted July 24, 2000; accepted January 30, 2001.
Supported by National Institutes of Health grants CA18029, CA 38926, CA32102, and K12-CA76930, and the Friends of Jose Carreras International Leukemia Foundation.
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.
Reprints: Derek L. Stirewalt, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA 98109; e-mail: dstirewa{at}fhcrc.org.
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© 2001 by The American Society of Hematology.
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  S. Fukuda, P. Singh, A. Moh, M. Abe, E. M. Conway, H. S. Boswell, S. Yamaguchi, X.-Y. Fu, and L. M. Pelus Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3 Blood, July 9, 2009; 114(2): 394 - 403. [Abstract] [Full Text] [PDF]
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 S. Meshinchi and F. R. Appelbaum Structural and Functional Alterations of FLT3 in Acute Myeloid Leukemia Clin. Cancer Res., July 1, 2009; 15(13): 4263 - 4269. [Abstract] [Full Text] [PDF]
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A. Nordigarden, M. Kraft, P. Eliasson, V. Labi, E. W.-F. Lam, A. Villunger, and J.-I. Jonsson BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3 Blood, March 5, 2009; 113(10): 2302 - 2311. [Abstract] [Full Text] [PDF]
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 H. D. Klepin and L. Balducci Acute Myelogenous Leukemia in Older Adults Oncologist, March 1, 2009; 14(3): 222 - 232. [Abstract] [Full Text] [PDF]
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 A. Neubauer, K. Maharry, K. Mrozek, C. Thiede, G. Marcucci, P. Paschka, R. J. Mayer, R. A. Larson, E. T. Liu, and C. D. Bloomfield Patients With Acute Myeloid Leukemia and RAS Mutations Benefit Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study J. Clin. Oncol., October 1, 2008; 26(28): 4603 - 4609. [Abstract] [Full Text] [PDF]
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J. P. Radich Molecular Classification of Acute Myeloid Leukemia: Are We There Yet? J. Clin. Oncol., October 1, 2008; 26(28): 4539 - 4541. [Full Text] [PDF]
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J. Laubach and A. V. Rao Current and Emerging Strategies for the Management of Acute Myeloid Leukemia in the Elderly Oncologist, October 1, 2008; 13(10): 1097 - 1108. [Abstract] [Full Text] [PDF]
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S. Meshinchi, D. L. Stirewalt, T. A. Alonzo, T. J. Boggon, R. B. Gerbing, J. L. Rocnik, B. J. Lange, D. G. Gilliland, and J. P. Radich Structural and numerical variation of FLT3/ITD in pediatric AML Blood, May 15, 2008; 111(10): 4930 - 4933. [Abstract] [Full Text] [PDF]
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R. Garzon, S. Volinia, C.-G. Liu, C. Fernandez-Cymering, T. Palumbo, F. Pichiorri, M. Fabbri, K. Coombes, H. Alder, T. Nakamura, et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia Blood, March 15, 2008; 111(6): 3183 - 3189. [Abstract] [Full Text] [PDF]
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A. Sallmyr, J. Fan, K. Datta, K.-T. Kim, D. Grosu, P. Shapiro, D. Small, and F. Rassool Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML Blood, March 15, 2008; 111(6): 3173 - 3182. [Abstract] [Full Text] [PDF]
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 T. Haferlach Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia Hematology, January 1, 2008; 2008(1): 400 - 411. [Abstract] [Full Text] [PDF]
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 A. C.H. de Vries, R. W. Stam, P. Schneider, C. M. Niemeyer, E. R. van Wering, O. A. Haas, C. P. Kratz, M. L. den Boer, R. Pieters, and M. M. van den Heuvel-Eibrink Role of mutation independent constitutive activation of FLT3 in juvenile myelomonocytic leukemia Haematologica, November 1, 2007; 92(11): 1557 - 1560. [Abstract] [Full Text] [PDF]
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D. C. Link, G. Kunter, Y. Kasai, Y. Zhao, T. Miner, M. D. McLellan, R. E. Ries, D. Kapur, R. Nagarajan, D. C. Dale, et al. Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia Blood, September 1, 2007; 110(5): 1648 - 1655. [Abstract] [Full Text] [PDF]
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P. Brown, E. McIntyre, R. Rau, S. Meshinchi, N. Lacayo, G. Dahl, T. A. Alonzo, M. Chang, R. J. Arceci, and D. Small The incidence and clinical significance of nucleophosmin mutations in childhood AML Blood, August 1, 2007; 110(3): 979 - 985. [Abstract] [Full Text] [PDF]
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S. Vempati, C. Reindl, S. K. Kaza, R. Kern, T. Malamoussi, M. Dugas, G. Mellert, S. Schnittger, W. Hiddemann, and K. Spiekermann Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential Blood, July 15, 2007; 110(2): 686 - 694. [Abstract] [Full Text] [PDF]
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U. Bacher, T. Haferlach, W. Kern, C. Haferlach, and S. Schnittger A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia Haematologica, June 1, 2007; 92(6): 744 - 752. [Abstract] [Full Text] [PDF]
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S. Meshinchi and R. J. Arceci Prognostic Factors and Risk-Based Therapy in Pediatric Acute Myeloid Leukemia Oncologist, March 1, 2007; 12(3): 341 - 355. [Abstract] [Full Text] [PDF]
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A. M. Pelizzari, M. Drera, M. D'Adda, M. Ungari, D. Marocolo, F. Facchetti, D. Bellotti, S. Barlati, and G. Rossi Recombinant granulocyte-colony stimulating factor as treatment for poor prognosis oligoblastic acute myeloid leukemia in elderly patients Haematologica, January 1, 2007; 92(1): 106 - 109. [Abstract] [Full Text] [PDF]
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J. Pedersen-Bjergaard, M. T. Andersen, and M. K. Andersen Genetic Pathways in the Pathogenesis of Therapy-Related Myelodysplasia and Acute Myeloid Leukemia Hematology, January 1, 2007; 2007(1): 392 - 397. [Abstract] [Full Text] [PDF]
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H. P. Erba Prognostic Factors in Elderly Patients with AML and the Implications for Treatment Hematology, January 1, 2007; 2007(1): 420 - 428. [Abstract] [Full Text] [PDF]
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S. Meshinchi, T. A. Alonzo, D. L. Stirewalt, M. Zwaan, M. Zimmerman, D. Reinhardt, G. J. L. Kaspers, N. A. Heerema, R. Gerbing, B. J. Lange, et al. Clinical implications of FLT3 mutations in pediatric AML Blood, December 1, 2006; 108(12): 3654 - 3661. [Abstract] [Full Text] [PDF]
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C. D. Bloomfield, K. Mrozek, and M. A. Caligiuri Cancer and Leukemia Group B Leukemia Correlative Science Committee: Major Accomplishments and Future Directions. Clin. Cancer Res., June 1, 2006; 12(11): 3564s - 3571s. [Abstract] [Full Text] [PDF]
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U. Bacher, T. Haferlach, C. Schoch, W. Kern, and S. Schnittger Implications of NRAS mutations in AML: a study of 2502 patients Blood, May 15, 2006; 107(10): 3847 - 3853. [Abstract] [Full Text] [PDF]
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D. L. Stirewalt, K. J. Kopecky, S. Meshinchi, J. H. Engel, E. L. Pogosova-Agadjanyan, J. Linsley, M. L. Slovak, C. L. Willman, and J. P. Radich Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia Blood, May 1, 2006; 107(9): 3724 - 3726. [Abstract] [Full Text] [PDF]
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 C. H. Brandts, B. Sargin, M. Rode, C. Biermann, B. Lindtner, J. Schwable, H. Buerger, C. Muller-Tidow, C. Choudhary, M. McMahon, et al. Constitutive Activation of Akt by Flt3 Internal Tandem Duplications Is Necessary for Increased Survival, Proliferation, and Myeloid Transformation Cancer Res., November 1, 2005; 65(21): 9643 - 9650. [Abstract] [Full Text] [PDF]
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T. Suzuki, H. Kiyoi, K. Ozeki, A. Tomita, S. Yamaji, R. Suzuki, Y. Kodera, S. Miyawaki, N. Asou, K. Kuriyama, et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia Blood, October 15, 2005; 106(8): 2854 - 2861. [Abstract] [Full Text] [PDF]
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D. T. Bowen, M. E. Frew, R. Hills, R. E. Gale, K. Wheatley, M. J. Groves, S. E. Langabeer, P. D. Kottaridis, A. V. Moorman, A. K. Burnett, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years Blood, September 15, 2005; 106(6): 2113 - 2119. [Abstract] [Full Text] [PDF]
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S. Frohling, C. Scholl, D. G. Gilliland, and R. L. Levine Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications J. Clin. Oncol., September 10, 2005; 23(26): 6285 - 6295. [Abstract] [Full Text] [PDF]
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T. Illmer, C. Thiede, A. Fredersdorf, S. Stadler, A. Neubauer, G. Ehninger, and M. Schaich Activation of the RAS Pathway Is Predictive for a Chemosensitive Phenotype of Acute Myelogenous Leukemia Blasts Clin. Cancer Res., May 1, 2005; 11(9): 3217 - 3224. [Abstract] [Full Text] [PDF]
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S. Fukuda, H. E. Broxmeyer, and L. M. Pelus Flt3 ligand and the Flt3 receptor regulate hematopoietic cell migration by modulating the SDF-1{alpha}(CXCL12)/CXCR4 axis Blood, April 15, 2005; 105(8): 3117 - 3126. [Abstract] [Full Text] [PDF]
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C. Recher, O. Beyne-Rauzy, C. Demur, G. Chicanne, C. Dos Santos, V. M.-D. Mas, D. Benzaquen, G. Laurent, F. Huguet, and B. Payrastre Antileukemic activity of rapamycin in acute myeloid leukemia Blood, March 15, 2005; 105(6): 2527 - 2534. [Abstract] [Full Text] [PDF]
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M. Wadleigh, D. J. DeAngelo, J. D. Griffin, and R. M. Stone After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies Blood, January 1, 2005; 105(1): 22 - 30. [Abstract] [Full Text] [PDF]
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K. Ozeki, H. Kiyoi, Y. Hirose, M. Iwai, M. Ninomiya, Y. Kodera, S. Miyawaki, K. Kuriyama, C. Shimazaki, H. Akiyama, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia Blood, March 1, 2004; 103(5): 1901 - 1908. [Abstract] [Full Text] [PDF]
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R. Zheng, M. Levis, O. Piloto, P. Brown, B. R. Baldwin, N. C. Gorin, M. Beran, Z. Zhu, D. Ludwig, D. Hicklin, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells Blood, January 1, 2004; 103(1): 267 - 274. [Abstract] [Full Text] [PDF]
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J. E. Lancet and J. E. Karp Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy Blood, December 1, 2003; 102(12): 3880 - 3889. [Abstract] [Full Text] [PDF]
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 T. J. Ley, P. J. Minx, M. J. Walter, R. E. Ries, H. Sun, M. McLellan, J. F. DiPersio, D. C. Link, M. H. Tomasson, T. A. Graubert, et al. A pilot study of high-throughput, sequence-based mutational profiling of primary human acute myeloid leukemia cell genomes PNAS, November 25, 2003; 100(24): 14275 - 14280. [Abstract] [Full Text] [PDF]
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C. M. Zwaan, S. Meshinchi, J. P. Radich, A. J. P. Veerman, D. R. Huismans, L. Munske, M. Podleschny, K. Hahlen, R. Pieters, M. Zimmermann, et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance Blood, October 1, 2003; 102(7): 2387 - 2394. [Abstract] [Full Text] [PDF]
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S. Meshinchi, D. L. Stirewalt, T. A. Alonzo, Q. Zhang, D. A. Sweetser, W. G. Woods, I. D. Bernstein, R. J. Arceci, and J. P. Radich Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia Blood, August 15, 2003; 102(4): 1474 - 1479. [Abstract] [Full Text] [PDF]
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A.-M. O'Farrell, T. J. Abrams, H. A. Yuen, T. J. Ngai, S. G. Louie, K. W. H. Yee, L. M. Wong, W. Hong, L. B. Lee, A. Town, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo Blood, May 1, 2003; 101(9): 3597 - 3605. [Abstract] [Full Text] [PDF]
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 R.K. WILSON, T.J. LEY, F.S. COLE, J.D. MILBRANDT, S. CLIFTON, L. FULTON, G. FEWELL, P. MINX, H. SUN, M. MCLELLAN, et al. Mutational Profiling in the Human Genome Cold Spring Harb Symp Quant Biol, January 1, 2003; 68(0): 23 - 30. [Abstract] [PDF]
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K. Neben, C. Giesecke, S. Schweizer, A. D. Ho, and A. Kramer Centrosome aberrations in acute myeloid leukemia are correlated with cytogenetic risk profile Blood, January 1, 2003; 101(1): 289 - 291. [Abstract] [Full Text] [PDF]
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M. L. Guzman, C. F. Swiderski, D. S. Howard, B. A. Grimes, R. M. Rossi, S. J. Szilvassy, and C. T. Jordan Preferential induction of apoptosis for primary human leukemic stem cells PNAS, December 10, 2002; 99(25): 16220 - 16225. [Abstract] [Full Text] [PDF]
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R. Zheng, A. D. Friedman, and D. Small Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations Blood, December 1, 2002; 100(12): 4154 - 4161. [Abstract] [Full Text] [PDF]
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M. T. Voso, F. D'Alo', R. Putzulu, L. Mele, A. Scardocci, P. Chiusolo, R. Latagliata, F. Lo-Coco, S. Rutella, L. Pagano, et al. Negative prognostic value of glutathione S-transferase (GSTM1 and GSTT1) deletions in adult acute myeloid leukemia Blood, September 26, 2002; 100(8): 2703 - 2707. [Abstract] [Full Text] [PDF]
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K. W. H. Yee, A. M. O'Farrell, B. D. Smolich, J. M. Cherrington, G. McMahon, C. L. Wait, L. S. McGreevey, D. J. Griffith, and M. C. Heinrich SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase Blood, September 26, 2002; 100(8): 2941 - 2949. [Abstract] [Full Text] [PDF]
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L.-Y. Shih, C.-F. Huang, J.-H. Wu, T.-L. Lin, P. Dunn, P.-N. Wang, M.-C. Kuo, C.-L. Lai, and H.-C. Hsu Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse Blood, September 18, 2002; 100(7): 2387 - 2392. [Abstract] [Full Text] [PDF]
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D. G. Gilliland and J. D. Griffin The roles of FLT3 in hematopoiesis and leukemia Blood, August 13, 2002; 100(5): 1532 - 1542. [Abstract] [Full Text] [PDF]
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L. M. Kelly, J. L. Kutok, I. R. Williams, C. L. Boulton, S. M. Amaral, D. P. Curley, T. J. Ley, and D. G. Gilliland PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model PNAS, June 11, 2002; 99(12): 8283 - 8288. [Abstract] [Full Text] [PDF]
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K. Inokuchi, H. Yamaguchi, H. Hanawa, S. Tanosaki, K. Nakamura, M. Tarusawa, K. Miyake, T. Shimada, and K. Dan Loss of DCC Gene Expression Is of Prognostic Importance in Acute Myelogenous Leukemia Clin. Cancer Res., June 1, 2002; 8(6): 1882 - 1888. [Abstract] [Full Text] [PDF]
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M. Levis, J. Allebach, K.-F. Tse, R. Zheng, B. R. Baldwin, B. D. Smith, S. Jones-Bolin, B. Ruggeri, C. Dionne, and D. Small A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo Blood, May 13, 2002; 99(11): 3885 - 3891. [Abstract] [Full Text] [PDF]
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S. K. Loftus, D. M. Larson, L. L. Baxter, A. Antonellis, Y. Chen, X. Wu, Y. Jiang, M. Bittner, J. A. Hammer III, and W. J. Pavan Mutation of melanosome protein RAB38 in chocolate mice PNAS, March 21, 2002; (2002) 72087599. [Abstract] [Full Text] [PDF]
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F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian Acute Myeloid Leukemia Hematology, January 1, 2002; 2002(1): 73 - 110. [Abstract] [Full Text]
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D. Grimwade, H. Walker, G. Harrison, F. Oliver, S. Chatters, C. J. Harrison, K. Wheatley, A. K. Burnett, and A. H. Goldstone The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial Blood, September 1, 2001; 98(5): 1312 - 1320. [Abstract] [Full Text] [PDF]
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F. R. Appelbaum, J. M. Rowe, J. Radich, and J. E. Dick Acute Myeloid Leukemia Hematology, January 1, 2001; 2001(1): 62 - 86. [Abstract] [Full Text] [PDF]
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S. K. Loftus, D. M. Larson, L. L. Baxter, A. Antonellis, Y. Chen, X. Wu, Y. Jiang, M. Bittner, J. A. Hammer III, and W. J. Pavan Mutation of melanosome protein RAB38 in chocolate mice PNAS, April 2, 2002; 99(7): 4471 - 4476. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
55 years) remains unsatisfactory, with reported long-term
survival less than 10%.
D) (single-letter amino
acid codes) change was the most frequent amino acid substitution (29%,
8 of 28 RAS mutations) and was particularly common in codon
13 (Figure 
1, guanosine
triphosphatase-activating protein, Shc, and Vav, some of which have
been linked to RAS pathways,
a possible pointer to their aetiology.
Leukemia Res.
1997;21:559-574