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Immunology |
The Ohio State University, Columbus, Ohio 43210 [S. P. W., K. J. A., L. F., C. B., B. B., B. D. C., K. M., C. D. B., M. A. C.]; The Cancer and Leukemia Group B Statistical Center, Durham, North Carolina 27710 [K. J. A., S. L. G.]; University of Alabama, Birmingham, Alabama 35249 [A. J. C.]; University of Chicago, Chicago, Illinois 60637 [J. W. V., R. A. L.]; and North Shore University Hospital, Manhasset, New York 11030 [J. E. K.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the initial report, length mutations in the FLT3 gene were detected that resulted from a partial ITD in 5 of 22 (22.7%) adults with AML (6) . Additional studies (6, 7, 8, 9) have confirmed this finding and have determined that the duplication involves the JM domain-coding sequence in a head-to-tail fashion that is always in-frame. In experimental systems, the FLT3 ITD leads to ligand-independent FLT3 dimerization and constitutive activation of the TK domains via autophosphorylation (10 , 11) . This in turn appears to constitutively activate signal transducers and activators of transcription 5 and mitogen-activated protein kinase and introduces autonomous cell growth in cytokine-dependent cell lines (11, 12, 13, 14) .
Two recent studies (8 , 15) have reported that the presence of the FLT3 ITD is associated with statistically significant worse clinical outcomes compared with patients not harboring this defect. In the latter study, the FLT3 ITD occurred in AML at a frequency of 22% in 81 cases studied and was associated with reduced DFS for cases with de novo AML or intermediate-risk cytogenetics (P = 0.004 and P = 0.008, respectively; Ref. 8 ). However, patients were treated with a variety of treatment regimens. A recent pediatric AML study (9) was performed on patients who were treated under one protocol. A modest but significant difference in OS was noted (P = 0.02) between FLT3 ITD cases and FLT3 WT pediatric cases, with the FLT3 ITD cases showing a poorer prognosis (9) . In all of the reports to date, the analysis of the FLT3 ITD mutation has consisted of its presence or absence by genomic or RT-PCR and sequence of its in-frame fusion. Hence, the mechanism by which this mutation may contribute to AML remains uncertain.
In the current study, we examined diagnostic bone marrow samples for the FLT3 ITD in 82 adults <60 years of age with de novo AML and normal cytogenetics who were treated on a single dose-intensive treatment protocol within the CALGB. We identified three distinct genotypes in our molecular analysis: normal FLT3WT/WT, heterozygous FLT3ITD/WT, and hemizygous FLT3ITD/-, i.e., FLT3 ITD-positive that also lacked the FLT3 WT allele. Our analysis indicates that the FLT3ITD/- patients have a significantly shortened survival when compared with FLT3WT/WT and/or FLT3ITD/WT patients. Therefore, the data are consistent with a FLT3 mutation and loss of WT allele resulting in a dominant-positive gain-of-function effect that is responsible for this phenotype.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Leukemias were classified morphologically according to the FAB Cooperative Group criteria. All of the cases were centrally reviewed. Chromosomal analysis of bone marrow was performed in institutional CALGB cytogenetics laboratories, and karyotypes were centrally reviewed biannually by an expert panel of CALGB cancer cytogeneticists as part of a prospective study of cytogenetics in acute leukemia, CALGB 8461 (18) . Specimens were obtained at diagnosis and processed using unstimulated short-term (24-h, 48-h, and 72-h) cultures. G banding was typically done, although Q banding was also acceptable for inclusion in this series. The criteria used to describe a cytogenetic clone and description of karyotypes followed the recommendations of the International System for Human Cytogenetic Nomenclature (19) . A minimum of 20 bone marrow metaphases/case were required to be examined for a case to be classified as having normal cytogenetics. Cells taken at diagnosis were also shipped via overnight express to the CALGB Leukemia Tissue Bank and were viably procured in liquid nitrogen after enrichment for mononuclear cells through a Ficoll gradient. Buccal swabs were often obtained from patients and snap-frozen for DNA extraction at the time of diagnosis.
Detection of a FLT3 ITD by DNA PCR and by RT-PCR.
DNA and RNA were extracted from thawed bone marrow samples by standard protocols (20)
. PCR and RT-PCR were carried out as described previously (6)
using primers that detect all of the length mutations discovered to date for the FLT3 gene. Amplification products after 35 PCR cycles were size fractionated through 2.5–3% agarose gels and viewed under UV illumination after ethidium bromide staining. In addition, longer range DNA PCRs were performed in the FLT3 gene extending from exon 10 to the 3'-end of exon 12. Each standard DNA PCR product was excised from gels and purified (Qiaquick; Qiagen, Inc., Valencia, CA). After TA cloning (Invitrogen, Inc., Carlsbad, CA), a minimum of 10 clones with insert DNA were sequenced by The Sequencing and Genotyping Unit of the Ohio State University Comprehensive Cancer Center (Columbus, OH). DNA was analyzed using the basic local alignment tool, BLAST. Amino acid sequences were aligned using the MegAlign software program of DNAStar.
LOH Analysis.
LOH was determined at chromosome 13 band q12 using fluorogenic primers that amplify the microsatellite markers D13S221, D13S1304, D13S1244, D13S1254, D13S1246, and D13S218 (Research Genetics, Inc., Huntsville, AL). The estimated location of these markers relative to the FLT3 gene locus is shown in Fig. 2B
. Markers also used that are outside this region were D13S175 at 13q11 and D13S1265 at 13q33. PCR was performed using primer pairs for each of these markers, and DNA was derived from leukemic bone marrow and buccal swab epithelial cells from the same patient. LOH analysis was performed on the sequenced PCR products using Genotyper 2.0 (The Sequencing and Genotyping Unit of the Ohio State University Comprehensive Cancer Center). Both positive and negative controls were run simultaneously.
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-level was adjusted to = 0.05 ÷ 3 = 0.0167 in assessing the significance of the pairwise comparisons.
CR required an absolute neutrophil count 
1,500/µl, a platelet count 100,000/µl, no leukemic blasts in the peripheral blood, bone marrow cellularity >20% with maturation of all of the cell lines, no auer rods, <5% bone marrow blast cells, and no extramedullary leukemia, with persistence for at least 1 month. Relapse was defined as the reappearance of circulating blast cells not attributable to "overshoot" after recovery from myelosuppressive therapy or >5% blasts in the marrow not attributable to another cause or development of extramedullary leukemia. DFS was defined only for patients who achieved CR and was measured from the documented date of CR until date of relapse or death regardless of cause, censoring for patients alive in continuous CR. OS was measured from the protocol on-study date until date of death, regardless of cause of death, censoring for patients alive. Median follow-up for survival for censored patients (i.e., patients still alive) was 1.7 years overall, 1.2 years for the FLT3ITD/- group, 2.0 years for the FLT3ITD/WT group, and 1.6 years for the FLT3WT/WT group. Kaplan-Meier curves were constructed for DFS and OS comparing the three FLT3 genotype groups. The log-rank test was performed to determine whether there was a significant difference between the survival curves.
Finally, to adjust for potential confounding covariates, a Cox proportional hazards model was built using a backwards variable selection procedure to determine whether genotype, as an indicator variable, remained significant as a prognostic factor once other covariates adjusted the model. Firstly, univariate models for each clinical characteristic at baseline were fit. Secondly, univariate models incorporating an artificial time-dependent covariate expressed as the product of the covariate and the log of the time variable were fit to assess whether the proportional hazards assumption was met. If the proportional hazards assumption was not met for a particular variable, then the artificial time-dependent covariate was included in all of the subsequent models containing that variable. Thereafter, variables reflecting a P from the likelihood ratio test in the univariate models of <0.20 were incorporated together in a full model. Variables reporting a P of >0.05 from the corresponding Wald statistic in the full model were subsequently dropped one at a time in determining the final model. Statistical analyses were performed by the CALGB Statistical Center.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; representative samples shown). Representative samples from FLT3ITD/WT and FLT3ITD/- patients were then subjected to RT-PCR (Fig. 1B)
. Results were completely consistent with those obtained by DNA PCR in that the WT FLT3 transcript levels were low to absent compared with the mutant FLT3 transcript in the FLT3ITD/- cases examined. To determine whether these results were indicative of a missing FLT3 WT allele, we performed a longer range DNA PCR, extending from exon 10 of the FLT3 gene to the end of exon 12. The results were consistent with the earlier DNA and RNA PCR results, in that there were again low to nondetectable levels of the WT PCR product in the FLT3ITD/- cases examined (Fig. 2A
; representative samples shown).
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. In all of the three FLT3ITD/- patients studied, LOH was observed in the region near the FLT3 locus. These data provide further evidence that the WT FLT3 allele is likely lost from the non-FLT3 ITD-containing chromosome 13 in these FLT3ITD/- cases. In a case where relatively low levels of WT FLT3 DNA and transcript were detected (Fig. 1, A–B
, Lane 2; and Fig. 2A
, Lane 7), LOH was shown to be present (Fig. 2B
, Patient 1), supporting that the observed WT FLT3 PCR products were likely amplified from contaminating normal cellular DNA in the samples. Interestingly, one marker, D13S1246, showed retention of heterozygosity, i.e., presence of two different alleles and thus two differing chromosomes, in pt 1, although the most distal marker, D13S1265, showed LOH, suggesting there are regions of microdeletions on one chromosome 13 in this patient case. Our analysis was consistent with three genotypes in this group of adult de novo AML with normal cytogenetics: 59 cases of AML with FLT3 WT alleles (FLT3WT/WT); 15 cases of AML with the FLT3 ITD in combination with the FLT3 WT allele (FLT3ITD/WT); eight cases of AML with the FLT3 ITD lacking a FLT3 WT allele (FLT3ITD/-).
Clinical Characteristics of AML Patients with FLT3WT/WT, FLT3ITD/WT, and FLT3ITD/- Genotypes.
First, we compared the clinical characteristics at presentation between the three groups followed by relevant pairwise comparisons. As noted earlier, all of the patients in this study had a normal karyotype on diagnostic bone marrow aspirates. There were no significant differences with respect to age, sex, FAB subtypes, or other clinical characteristics such as gum hypertrophy, lymphadenopathy, splenomegaly, or hepatomegaly across the three groups (Table 1)
. The median WBCs increased from 16.3 x 109/liter in patients within the FLT3WT/WT group to 56.9 x 109/liter in the FLT3ITD/WT group and was highest in the FLT3ITD/- group (75.2 x 109/liter; P = 0.01). The trend of an increase in percentage of peripheral blood leukemic blasts in the three groups did not reach statistical significance (P = 0.05).
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). Failure to achieve CR in two FLT3ITD/- patients resulted from primary resistant disease as it did in three FLT3ITD/WT patients. However, failure to achieve CR in the FLT3WT/WT patients was because of primary resistant disease in four patients and death during induction in four patients.
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). DFS was significantly shorter for the FLT3ITD/- group compared with the FLT3WT/WT group (P = 0.0008) and borderline shorter for the FLT3ITD/WT group (P = 0.025; Table 3
). Furthermore, five of the six (83%) FLT3ITD/- patients who achieved CR relapsed at a median of 3 months. In contrast, 4 (36%) of the 11 FLT3ITD/WT group have relapsed and 10 of the 51 (20%) FLT3WT/WT group have relapsed at a median of 9 and 8 months, respectively. The relapse rate is significantly different among the three groups (P = 0.0026; Fisher’s exact test).
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). The OS rate at 12 months was 74% for the FLT3WT/WT group, 65% for FLT3ITD/WT group, and 13% for the FLT3ITD/- group (Table 2)
. The FLT3ITD/- group had a much shorter OS when compared with the FLT3ITD/WT group (P = 0.008) and the FLT3WT/WT group (P = 0.0005; Table 3
). There was no difference in OS between the FLT3WT/WT and FLT3ITD/WT groups (P = 0.98). Importantly, there was no difference in OS when comparing patients with and without a FLT3 ITD (i.e., FLT3WT/WT group versus combined FLT3ITD/WT and FLT3ITD/- groups; P = 0.14; Table 4
). This is in contrast to several earlier reports (8
, 21)
. The data indicate the group of patients that lack a WT FLT3 allele in association with the FLT3 ITD have a significantly inferior outcome in OS (i.e., FLT3WT/WT + FLT3ITD/WT groups versus FLT3ITD/- group; P = 0.0003; Table 5
).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We have identified at least three distinct genotypes of the FLT3 locus: FLT3WT/WT, FLT3ITD/WT, and FLT3ITD/-. The hemizygous FLT3ITD/- had been detected previously in one (1.1%) of 91 children with AML (8) and in four (4.9%) of 81 adult AML patients (7) . However, the AML patient populations studied were cytogenetically heterogeneous and included patients with karyotypes conferring poor, intermediate, and favorable prognosis. When we restricted our analysis to adults younger than 60 with a normal karyotype, the FLT3ITD/- was detected in nearly 10% of all of the patients analyzed and 35% of all of the cases with a FLT3 ITD allele. The first evidence that the FLT3ITD/- genotype might be associated with a distinct phenotype came from the analysis of clinical outcome, demonstrating that this subset of uniformly treated relatively young adult AML patients with normal cytogenetics had a significantly unfavorable outcome despite their otherwise "standard risk" profile.
No difference in overall survival was found between the FLT3WT/WT group and the FLT3ITD/WT group, alone or in combination with the FLT3ITD/- group. How can this be explained? In the absence of a WT FLT3 allele, a myeloblast with the FLT3 ITD mutant homodimers could continuously as well as aberrantly activate downstream signaling pathways (26)
, when compared to myeloblasts with either the FLT3WT/WT or FLT3ITD/WT genotype (see Fig. 4
). In this regard, a single amino acid substitution in the JM domain of the related receptor, PDGFR, causes constitutive kinase activity, and changes in the JM domain of PDGFR alter downstream docking sites for proteins that normally bind to the activated WT receptor (27
, 28)
. In the FLT3ITD/WT cases, presence of the WT FLT3 has the potential to diminish the effect of the FLT3 ITD, whereas signal transduction by constitutively active FLT3 ITD homodimers in the FLT3ITD/- cases could enhance myeloblast survival and cell cycling, priming the cell for secondary molecular events contributing to malignant transformation and chemoresistance. Indeed, seven of the eight patients with the FLT3ITD/- genotype and otherwise intermediate risk had either refractory AML or relapsed shortly after one or two cycles of consolidation therapy. Therefore, this report identifies a subset of relatively young adult AML patients (median age of 37) with a normal karyotype and FLT3ITD/- genotype that has an especially poor prognosis despite dose-intensive chemotherapy. Because this is a relatively small study, a larger study of the kind we have presented could provide additional strength to our conclusions, especially as to whether the FLT3WT/WT and FLT3ITD/WT genotypes still have relatively similar outcomes after longer follow-up data are obtained. Moreover, it will also be interesting to examine cases we have defined as FLT3WT/WT and FLT3ITD/WT for evidence of an activating point mutation (29)
, recently discovered in 8 of 201 (4%) de novo AML cases, to determine whether its presence impacts our results.
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. Moreover, careful review of karyotypes of all eight patients with FLT3ITD/- revealed that in two of them, including patient 3 in Fig. 2B
, the two homologous chromosomes clearly differed morphologically with regard to the heteromorphic regions in their short arms. Thus, we believe that duplication of the chromosome 13 homologue containing the FLT3 ITD allele has likely not taken place in these three patients. On the other hand, LOH of several markers, including D13S175 mapped to 13q11 and D13S1265 mapped to 13q33, suggests a high degree of genetic instability in morphologically normal chromosomes 13 in this subset of patients with AML. We are investigating this further, along with the possibility that a subset of the FLT3WT/WT cases may, in actuality, have a FLT3WT/- genotype as well as the possibility that LOH has occurred elsewhere on chromosomes 13 near the FLT3 locus in cases with either the FLT3WT/WT or FLT3ITD/WT genotype. There appears to be a greater number of FLT3ITD/WT AML patients than FLT3ITD/- AML patients in all of the series reported to date, and our data show no clear adverse impact on OS or DFS in the former group compared with FLT3WT/WT patients. Therefore, it seems reasonable to speculate that the FLT3 ITD somatic mutation likely occurs before the loss of the FLT3 WT allele and that it may in some way contribute to the latter event, possibly through the induction of genomic instability. Further analysis of the FLT3 locus by fluorescence in situ hybridization or LOH analysis in AML cases that lack the FLT3 ITD might provide additional insight into this possibility.
The identification of a new subset of poor prognosis patients in AML patients without karyotypic abnormalities is important for directing early aggressive therapeutic alternatives for this otherwise "standard risk" group of patients. However, it is especially important given the nature of their molecular defect. The aberrant kinase activity that is likely maximized in the hemizygous cases would certainly suggest that therapy with a TK inhibitor specific for FLT3 should be beneficial to these unfortunate patients, the same way STI571 has been beneficial in patients with stable phase chronic myelogenous leukemia (30) . Such targeted therapies are in development at this time and might need to be directed to this specific subset of AML patients to demonstrate a significant impact on the disease. It is possible, however, that the other molecular defects arising before or after this mutation will require targeting as well. Perhaps allogeneic stem cell transplantation with a suitable donor should be incorporated into the primary induction regimen for these patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 CALGB 9621 was supported in part by Grant CA31946, CA77658, CA16058 from the National Cancer Institute and a Grant from the Coleman Leukemia Research Fund (to M. A. C.). S. P. W. is supported by a T-32 Oncology Training Grant CA09338 from the National Cancer Institute. S. L. G. is supported by CA3360. A. J. C. is supported by CA47545. J. W. V. and R. A. L. are supported by CA41287. J. E. K. is supported by CA35279. 
2 To whom requests for reprints should be addressed, at The Ohio State University, A458 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: (614) 293-7521; Fax: (614) 293-7522; E-mail: caligiuri-1{at}medctr.osu.edu
3 The abbreviations used are: RTK, receptor tyrosine kinase; JM, juxtamembrane; FL, FLT3 ligand; AML, acute myeloid leukemia; ITD, internal tandem duplication; DFS, disease-free survival; OS, overall survival; WT, wild-type; RT-PCR, reverse transcription-PCR; CALGB, Cancer and Leukemia Group B; PCST, peripheral blood stem cell transplant; LOH, loss of heterozygosity; CR, complete remission; FAB, French-American-British.
Received 5/11/01. Accepted 7/26/01.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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D. J. DeAngelo, R. M. Stone, M. L. Heaney, S. D. Nimer, R. L. Paquette, R. B. Klisovic, M. A. Caligiuri, M. R. Cooper, J.-M. Lecerf, M. D. Karol, et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics Blood, December 1, 2006; 108(12): 3674 - 3681. [Abstract] [Full Text] [PDF]
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S. Knapper, K. I. Mills, A. F. Gilkes, S. J. Austin, V. Walsh, and A. K. Burnett The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases Blood, November 15, 2006; 108(10): 3494 - 3503. [Abstract] [Full Text] [PDF]
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J. A. Pollard, T. A. Alonzo, R. B. Gerbing, W. G. Woods, B. J. Lange, D. A. Sweetser, J. P. Radich, I. D. Bernstein, and S. Meshinchi FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemia Blood, October 15, 2006; 108(8): 2764 - 2769. [Abstract] [Full Text] [PDF]
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M. D. Radmacher, G. Marcucci, A. S. Ruppert, K. Mrozek, S. P. Whitman, J. W. Vardiman, P. Paschka, T. Vukosavljevic, C. D. Baldus, J. E. Kolitz, et al. Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study Blood, September 1, 2006; 108(5): 1677 - 1683. [Abstract] [Full Text] [PDF]
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S. S. Farag, K. J. Archer, K. Mrozek, A. S. Ruppert, A. J. Carroll, J. W. Vardiman, M. J. Pettenati, M. R. Baer, M. B. Qumsiyeh, P. R. Koduru, et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461 Blood, July 1, 2006; 108(1): 63 - 73. [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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C. Thiede, S. Koch, E. Creutzig, C. Steudel, T. Illmer, M. Schaich, G. Ehninger, and for the Deutsche Studieninitiative Leukamie (DSIL) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML) Blood, May 15, 2006; 107(10): 4011 - 4020. [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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Z. Zeng, I. J. Samudio, W. Zhang, Z. Estrov, H. Pelicano, D. Harris, O. Frolova, N. Hail Jr., W. Chen, S. M. Kornblau, et al. Simultaneous Inhibition of PDK1/AKT and Fms-Like Tyrosine Kinase 3 Signaling by a Small-Molecule KP372-1 Induces Mitochondrial Dysfunction and Apoptosis in Acute Myelogenous Leukemia. Cancer Res., April 1, 2006; 66(7): 3737 - 3746. [Abstract] [Full Text] [PDF]
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 H. S. Radomska, D. S. Basseres, R. Zheng, P. Zhang, T. Dayaram, Y. Yamamoto, D. W. Sternberg, N. Lokker, N. A. Giese, S. K. Bohlander, et al. Block of C/EBP{alpha} function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations J. Exp. Med., February 21, 2006; 203(2): 371 - 381. [Abstract] [Full Text] [PDF]
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C. D. Baldus, C. Thiede, S. Soucek, C. D. Bloomfield, E. Thiel, and G. Ehninger BAALC Expression and FLT3 Internal Tandem Duplication Mutations in Acute Myeloid Leukemia Patients With Normal Cytogenetics: Prognostic Implications J. Clin. Oncol., February 10, 2006; 24(5): 790 - 797. [Abstract] [Full Text] [PDF]
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G. Marcucci, C. D. Baldus, A. S. Ruppert, M. D. Radmacher, K. Mrozek, S. P. Whitman, J. E. Kolitz, C. G. Edwards, J. W. Vardiman, B. L. Powell, et al. Overexpression of the ETS-Related Gene, ERG, Predicts a Worse Outcome in Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study J. Clin. Oncol., December 20, 2005; 23(36): 9234 - 9242. [Abstract] [Full Text] [PDF]
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K. Dohner, R. F. Schlenk, M. Habdank, C. Scholl, F. G. Rucker, A. Corbacioglu, L. Bullinger, S. Frohling, H. Dohner, and for the AML Study Group (AMLSG) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations Blood, December 1, 2005; 106(12): 3740 - 3746. [Abstract] [Full Text] [PDF]
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R. E. Gale, R. Hills, P. D. Kottaridis, S. Srirangan, K. Wheatley, A. K. Burnett, and D. C. Linch No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials Blood, November 15, 2005; 106(10): 3658 - 3665. [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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J. Fitzgibbon, L.-L. Smith, M. Raghavan, M. L. Smith, S. Debernardi, S. Skoulakis, D. Lillington, T. A. Lister, and B. D. Young Association between Acquired Uniparental Disomy and Homozygous Gene Mutation in Acute Myeloid Leukemias Cancer Res., October 15, 2005; 65(20): 9152 - 9154. [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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X. Yang, L. Liu, D. Sternberg, L. Tang, I. Galinsky, D. DeAngelo, and R. Stone The FLT3 Internal Tandem Duplication Mutation Prevents Apoptosis in Interleukin-3-Deprived BaF3 Cells Due to Protein Kinase A and Ribosomal S6 Kinase 1-Mediated BAD Phosphorylation at Serine 112 Cancer Res., August 15, 2005; 65(16): 7338 - 7347. [Abstract] [Full Text] [PDF]
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M. Levis, K. M. Murphy, R. Pham, K.-T. Kim, A. Stine, L. Li, I. McNiece, B. D. Smith, and D. Small Internal tandem duplications of the FLT3 gene are present in leukemia stem cells Blood, July 15, 2005; 106(2): 673 - 680. [Abstract] [Full Text] [PDF]
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S. P. Whitman, S. Liu, T. Vukosavljevic, L. J. Rush, L. Yu, C. Liu, M. I. Klisovic, K. Maharry, M. Guimond, M. P. Strout, et al. The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy Blood, July 1, 2005; 106(1): 345 - 352. [Abstract] [Full Text] [PDF]
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K. Bagrintseva, S. Geisenhof, R. Kern, S. Eichenlaub, C. Reindl, J. W. Ellwart, W. Hiddemann, and K. Spiekermann FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L) Blood, May 1, 2005; 105(9): 3679 - 3685. [Abstract] [Full Text] [PDF]
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A. Wolfler, S. J. Erkeland, C. Bodner, M. Valkhof, W. Renner, C. Leitner, W. Olipitz, M. Pfeilstocker, C. Tinchon, W. Emberger, et al. A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome Blood, May 1, 2005; 105(9): 3731 - 3736. [Abstract] [Full Text] [PDF]
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S. S. Farag, A. S. Ruppert, K. Mrozek, R. J. Mayer, R. M. Stone, A. J. Carroll, B. L. Powell, J. O. Moore, M. J. Pettenati, P. R.K. Koduru, et al. Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study J. Clin. Oncol., January 20, 2005; 23(3): 482 - 493. [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. W. H. Yee, M. Schittenhelm, A.-M. O'Farrell, A. R. Town, L. McGreevey, T. Bainbridge, J. M. Cherrington, and M. C. Heinrich Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells Blood, December 15, 2004; 104(13): 4202 - 4209. [Abstract] [Full Text] [PDF]
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N. J. Lacayo, S. Meshinchi, P. Kinnunen, R. Yu, Y. Wang, C. M. Stuber, L. Douglas, R. Wahab, D. L. Becton, H. Weinstein, et al. Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes Blood, November 1, 2004; 104(9): 2646 - 2654. [Abstract] [Full Text] [PDF]
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J. J. Clark, J. Cools, D. P. Curley, J.-C. Yu, N. A. Lokker, N. A. Giese, and D. G. Gilliland Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518 Blood, November 1, 2004; 104(9): 2867 - 2872. [Abstract] [Full Text] [PDF]
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P. Brown, S. Meshinchi, M. Levis, T. A. Alonzo, R. Gerbing, B. Lange, R. Arceci, and D. Small Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition Blood, September 15, 2004; 104(6): 1841 - 1849. [Abstract] [Full Text] [PDF]
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Y. H. Min, J.-W. Cheong, J. Y. Kim, J. I. Eom, S. T. Lee, J. S. Hahn, Y. W. Ko, and M. H. Lee Cytoplasmic Mislocalization of p27Kip1 Protein Is Associated with Constitutive Phosphorylation of Akt or Protein Kinase B and Poor Prognosis in Acute Myelogenous Leukemia Cancer Res., August 1, 2004; 64(15): 5225 - 5231. [Abstract] [Full Text] [PDF]
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 P. Saussoy, J.-L. Vaerman, N. Straetmans, V. Deneys, G. Cornu, A. Ferrant, and D. Latinne Differentiation of Acute Myeloid Leukemia from B- and T-Lineage Acute Lymphoid Leukemias by Real-Time Quantitative Reverse Transcription-PCR of Lineage Marker mRNAs Clin. Chem., July 1, 2004; 50(7): 1165 - 1173. [Abstract] [Full Text] [PDF]
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M. Grever Pharmacodynamics provide critical insight in drug development Blood, May 15, 2004; 103(10): 3614 - 3614. [Full Text] [PDF]
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B. D. Smith, M. Levis, M. Beran, F. Giles, H. Kantarjian, K. Berg, K. M. Murphy, T. Dauses, J. Allebach, and D. Small Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia Blood, May 15, 2004; 103(10): 3669 - 3676. [Abstract] [Full Text] [PDF]
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K. Bagrintseva, R. Schwab, T. M. Kohl, S. Schnittger, S. Eichenlaub, J. W. Ellwart, W. Hiddemann, and K. Spiekermann Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells Blood, March 15, 2004; 103(6): 2266 - 2275. [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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S. Frohling, R. F. Schlenk, I. Stolze, J. Bihlmayr, A. Benner, S. Kreitmeier, K. Tobis, H. Dohner, and K. Dohner CEBPA Mutations in Younger Adults With Acute Myeloid Leukemia and Normal Cytogenetics: Prognostic Relevance and Analysis of Cooperating Mutations J. Clin. Oncol., February 15, 2004; 22(4): 624 - 633. [Abstract] [Full Text] [PDF]
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D. Perrotti, G. Marcucci, and M. A. Caligiuri Loss of C/EBP{alpha} and Favorable Prognosis of Acute Myeloid Leukemias: A Biological Paradox J. Clin. Oncol., February 15, 2004; 22(4): 582 - 584. [Full Text] [PDF]
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L.-Y. Shih, C.-F. Huang, J.-H. Wu, P.-N. Wang, T.-L. Lin, P. Dunn, M.-C. Chou, M.-C. Kuo, and C.-C. Tang Heterogeneous Patterns of FLT3 Asp835 Mutations in Relapsed de Novo Acute Myeloid Leukemia: A Comparative Analysis of 120 Paired Diagnostic and Relapse Bone Marrow Samples Clin. Cancer Res., February 15, 2004; 10(4): 1326 - 1332. [Abstract] [Full Text] [PDF]
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B. D. Cheson, J. M. Bennett, K. J. Kopecky, T. Buchner, C. L. Willman, E. H. Estey, C. A. Schiffer, H. Doehner, M. S. Tallman, T. A. Lister, et al. Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia J. Clin. Oncol., December 15, 2003; 21(24): 4642 - 4649. [Abstract] [Full Text] [PDF]
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Y. Minami, K. Yamamoto, H. Kiyoi, R. Ueda, H. Saito, and T. Naoe Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia Blood, October 15, 2003; 102(8): 2969 - 2975. [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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C. D. Baldus, S. M. Tanner, A. S. Ruppert, S. P. Whitman, K. J. Archer, G. Marcucci, M. A. Caligiuri, A. J. Carroll, J. W. Vardiman, B. L. Powell, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study Blood, September 1, 2003; 102(5): 1613 - 1618. [Abstract] [Full Text] [PDF]
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K. Spiekermann, K. Bagrintseva, R. Schwab, K. Schmieja, and W. Hiddemann Overexpression and Constitutive Activation of FLT3 Induces STAT5 Activation in Primary Acute Myeloid Leukemia Blast Cells Clin. Cancer Res., June 1, 2003; 9(6): 2140 - 2150. [Abstract] [Full Text] [PDF]
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K. M. Murphy, M. Levis, M. J. Hafez, T. Geiger, L. C. Cooper, B.D. Smith, D. Small, and K. D. Berg Detection of FLT3 Internal Tandem Duplication and D835 Mutations by a Multiplex Polymerase Chain Reaction and Capillary Electrophoresis Assay J. Mol. Diagn., May 1, 2003; 5(2): 96 - 102. [Abstract] [Full Text] [PDF]
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M. Mizuki, J. Schwable, C. Steur, C. Choudhary, S. Agrawal, B. Sargin, B. Steffen, I. Matsumura, Y. Kanakura, F. D. Bohmer, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations Blood, April 15, 2003; 101(8): 3164 - 3173. [Abstract] [Full Text] [PDF]
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K. Spiekermann, R. J. Dirschinger, R. Schwab, K. Bagrintseva, F. Faber, C. Buske, S. Schnittger, L. M. Kelly, D. G. Gilliland, and W. Hiddemann The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3 Blood, February 15, 2003; 101(4): 1494 - 1504. [Abstract] [Full Text] [PDF]
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B. Lowenberg, J. D. Griffin, and M. S. Tallman Acute Myeloid Leukemia and Acute Promyelocytic Leukemia Hematology, January 1, 2003; 2003(1): 82 - 101. [Abstract] [Full Text] [PDF]
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J. C. Byrd, K. Mrozek, R. K. Dodge, A. J. Carroll, C. G. Edwards, D. C. Arthur, M. J. Pettenati, S. R. Patil, K. W. Rao, M. S. Watson, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461) Blood, December 15, 2002; 100(13): 4325 - 4336. [Abstract] [Full Text] [PDF]
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S. Frohling, R. F. Schlenk, J. Breitruck, A. Benner, S. Kreitmeier, K. Tobis, H. Dohner, and K. Dohner Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm Blood, December 15, 2002; 100(13): 4372 - 4380. [Abstract] [Full Text] [PDF]
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K. Spiekermann, K. Bagrintseva, C. Schoch, T. Haferlach, W. Hiddemann, and S. Schnittger A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia Blood, October 16, 2002; 100(9): 3423 - 3425. [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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S. Schnittger, C. Schoch, M. Dugas, W. Kern, P. Staib, C. Wuchter, H. Loffler, C. M. Sauerland, H. Serve, T. Buchner, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease Blood, June 17, 2002; 100(1): 59 - 66. [Abstract] [Full Text] [PDF]
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C. Thiede, C. Steudel, B. Mohr, M. Schaich, U. Schakel, U. Platzbecker, M. Wermke, M. Bornhauser, M. Ritter, A. Neubauer, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis Blood, May 29, 2002; 99(12): 4326 - 4335. [Abstract] [Full Text] [PDF]
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R. L. Schilsky, L. M. Dressler, D. Bucci, L. Monovich, S. Jewell, S. Suster, M. A. Caligiuri, P. W. Kantoff, and C. Compton Cooperative Group Tissue Banks As Research Resources: The Cancer and Leukemia Group B Tissue Repositories Clin. Cancer Res., May 1, 2002; 8(5): 943 - 948. [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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