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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From The Fred Hutchinson Cancer Research Center, and
University of Washington Medical Center, Seattle, WA; South Carolina
Cancer Center, Columbia, SC; University of Southern California School
of Medicine, Los Angeles, CA; National Childhood Cancer Foundation,
Arcadia, CA; and Children's Cancer Group, Pasadena, CA.
The Flt3 gene encodes a tyrosine kinase receptor that
regulates proliferation and differentiation of hematopoietic stem
cells. An internal tandem duplication of the Flt3 gene
(Flt3/ITD) has been reported in acute myelogenous leukemia (AML) and
may be associated with poor prognosis. We analyzed diagnostic bone
marrow specimens from 91 pediatric patients with AML treated on
Children's Cancer Group (CCG)-2891 for the presence of the Flt3/ITD
and correlated its presence with clinical outcome. Fifteen of 91 samples (16.5%) were positive for the Flt3/ITD. Flt3/ITD-positive
patients had a median diagnostic white count of 73 800 compared with
28 400 for the Flt3/ITD-negative patients (P = .05). The
size of the duplication ranged from 21 to 174 base pairs (bp).
Nucleotide sequencing of the abnormal polymerase chain reaction
products demonstrated that all duplications involved exon 11 of the
Flt3 gene and also preserved the reading frame. Lineage
restriction analysis revealed that Flt3/ITD was not present in the
lymphocytes, suggesting a lack of stem cell involvement for this
mutation. None of the Flt3/ITD-positive patients had unfavorable
cytogenetic markers, and there was no predominance of a particular FAB
class. The remission induction rate was 40% in Flt3/ITD-positive
patients compared with 74% in Flt3/ITD-negative ones
(P = .005). The Kaplan-Meier estimates of event-free
survival at 8 years for patients with and without Flt3/ITD were 7% and
44%, respectively (P = .002). Multivariate analysis
demonstrated that presence of the Flt3/ITD was the single most
significant, independent prognostic factor for poor outcome
(P = .009) in pediatric AML.
(Blood. 2001;97:89-94) Flt3 is a member of the class III tyrosine kinase
receptor family that includes the c-kit, c-fms,
and PDGF receptors. The Flt3 receptor is preferentially expressed on
hematopoietic stem cells and mediates stem cell differentiation and
proliferation.1 Interaction of the Flt3 receptor with Flt3
ligand causes receptor dimerization, leading to the activation of the
receptor tyrosine kinase and receptor
autophosphorylation.2 The phosphorylated Flt3 transduces
activation signals through association with various cytoplasmic
proteins, including ras GTPase-activating protein, phospholipase C, and Src family tyrosine kinases.3
Activation of the Flt3 receptor by ligand-dependent phosphorylation
induces cellular proliferation via activation of cytoplasmic mediators. It has also been demonstrated that Flt3 receptor activation causes proliferation of AML cells in vitro, as it appears to both stimulate proliferation and inhibit apoptosis of the AML cells.4
Thus, constitutive activation of the Flt3 pathway may lead to disease proliferation and may block the cellular apoptotic response to conventional chemotherapy.
An internal tandem duplication of the juxtamembrane (JM)
domain-coding sequence of the Flt3 (Flt3/ITD) gene on
chromosome 13 has been identified in a group of patients with
AML.5 In the Flt3/ITD, a fragment of the JM domain-coding
sequence (exons 11 and 12) is duplicated in direct head-to-tail
orientation. The length of the ITD varies, but the duplicated sequence
is always in-frame.5,6 In vitro studies have shown that
mutant Flt3/ITD receptors are dimerized in a ligand-independent
manner, leading to autophosphorylation of the receptor through
constitutive activation of the tyrosine kinase moieties.7
Such constitutive activation leads to autonomous, cytokine-independent
growth in the mutant cells.8
Flt3 mutations have been implicated in the pathogenesis of AML.
The Flt3/ITD has been associated with leukocytosis in acute promyelocytic leukemia.9 There is also evidence to suggest that Flt3/ITD is associated with leukemic transformation of
myelodysplasia.10 Few studies have examined the prognostic
significance of this mutation. Two adult studies demonstrated that the
presence of the Flt3/ITD was associated with poor
outcome.11,12 More recently, a small study of 56 pediatric
AML cases showed that children with Flt3/ITD had significantly worse
outcomes than children without this mutation.13 However,
the prognostic significance of this mutation remains uncertain, as the
patients studied were treated on numerous different treatment
protocols. Also, patients who received bone marrow transplantation were
censored from these studies, thus the impact of transplantation on
outcome was not examined. In this study we determined the prevalence
and prognostic significance of Flt3/ITD in a group of pediatric
patients with AML who were treated on the same treatment protocol, and
correlated its presence with clinical characteristics and outcome. We
also assessed the stem cell involvement of this mutation by determining the presence of this mutation in lymphocytes and myeloblasts.
Patients and treatments
Treatment protocol CCG-2891 has been described in detail
elsewhere.14-16 In brief, CCG-2891 is a prospective
randomized trial in which pediatric patients with AML were randomized
at diagnosis to receive one of 2 induction regimens involving 4-day
cycles of 5 chemotherapeutic agents (daunomycin, cytarabine, etoposide, 6-thioguanine, and dexamethasone). The second cycle was administered either after 10 days, despite low counts (intensive timing), or after
14 days, depending on the marrow status (standard timing). Induction
consisted of a total of 4 courses in both groups. At the end of
induction, patients who achieved remission and had a compatible
matched-related donor went on to receive allogeneic bone marrow
transplant (BMT). Patients without related donors were randomized to
either nonmyeloablative chemotherapy or an autologous BMT.
Analysis of the Flt3/ITD
Direct nucleotide sequencing of the amplified fragments Bands cut out from polyacrylamide gel were incubated overnight at room temperature in DEPC-H2O to extract double-stranded DNA (dsDNA) from the gel. The extracted dsDNA was directly sequenced using the Thermo Sequence Dye Terminator sequencing reaction.17Flow cytometric isolation of lymphocytes Lymphocytes were isolated by incubating diagnostic bone marrow samples with murine anti-CD3 and anti-CD20 antibodies, respectively, followed by FITC-conjugated goat antimurine antibody (Kirkegaard & Perry Laboratories, Gaithersburg, MD) and flow cytometry as previously described.18 DNA was extracted from the sorted cells using the Puregene protocol (Gentra Systems Inc).Statistical methods The distributions of categorical and continuous variables were compared between Flt3/ITD-positive and Flt3/ITD-negative groups. Statistical comparisons between the study group and the CCG-2891 population were also made. Pearson chi-square statistic was used to test for differences in the distribution of categorical variables. Analysis of variance was used to test for differences in the means of distributions. The Wilcox and rank sum test was used to test for differences in the medians of continuous variables.Nonparametric survival curves for censored data were computed by the Kaplan-Meier method.19 The significance of predictor variables was tested with the log-rank statistic. Significant predictors from univariate tests were studied with a Cox proportional hazards model.20 Variables were added in a step-wise manner, starting with variables known to be significant predictors from earlier studies. The likelihood-ratio statistic was used to test for the significance of model variables. Two-way interactions between predictor variables were also tested in this fashion.
Patient characteristics
Genomic polymerase chain reaction and sequence analysis of the Flt3 gene Genomic DNA was obtained from the diagnostic marrow specimens of 91 pediatric patients with AML and exons 11 and 12 of the Flt3 gene were amplified by PCR (Figure 1). The Flt3/ITD amplification yields a higher-molecular weight product on polyacrylamide gel electrophoresis (Figure 1, lanes 4 and 7). Fifteen of 91 patients (16.5%) tested had the Flt3/ITD, all confirmed by sequence analysis. Fourteen patients demonstrated both a normal and an aberrant band. One patient (Figure 1, lane 4) had a single aberrant PCR product indicative of the Flt3/ITD. This patient was previously shown to have a loss of heterozygosity (LOH) of chromosome 13 in the region containing the Flt3 gene. The size of the duplicated region varied from 21- to 174-base pairs (bp). Exon 11 of the Flt3 gene was involved in every patient, and in 2 patients, it extended to exon 12. In 2 patients, insertions of 6- and 15-bp were noted between the duplicated regions. In all cases, duplications maintained the integrity of the reading frame.
Lineage restriction of Flt3/ITD To determine whether the Flt3/ITD occurs at the level of the stem cell, lymphocytes from Flt3/ITD-positive patients were sorted from the diagnostic marrow specimens. DNA from the lymphocyte fractions was tested for the presence of the Flt3/ITD and compared with the blast population. Presence of the Flt3/ITD was restricted to the myeloblasts and was not detected in lymphocyte fractions tested (Figure 2), demonstrating the lack of involvement of the stem cell compartment.
Clinical characteristics of the study population Clinical characteristics of patients with and without the Flt3/ITD were compared (Table 3). There was no significant difference in the age of patients (P = .46), although it was noted that, of the 15 patients younger than 3 years in the study, none had the Flt3/ITD mutation. Patients with the Flt3/ITD had a diagnostic WBC of 73 800/µL compared with 28 400/µL for the patients without the mutation (P = .05).
Characteristics of patients with Flt3/ITD The parameters of age, WBC at diagnosis, induction regimen, FAB classification, cytogenetic abnormalities, clinical outcome, and the size of the duplication for the 15 patients with the Flt3/ITD are shown in Table 4. On average, this group of patients had a substantially higher WBC, although there were 4 patients who had WBC less than 20 000/µL. There was not a predominance of a particular FAB class in Flt3/ITD-positive patients, though FAB classes M5, M6, or M7 were not represented. None of the 15 patients with Flt3/ITD had unfavorable cytogenetic markers. One patient had an 11q23 translocation, which in CCG-2891, it was not found to be of prognostic significance. There were 4 patients (27%) with t(15;17), inv 16, or t(8;21) translocation traditionally considered as favorable cytogenetic markers. This compares with a prevalence of 29% (22 patients) in patients without the Flt3/ITD.
Clinical outcome and evaluation of prognostic factors Clinical outcome was determined for patients with and without the Flt3/ITD. The remission induction rate was 40% for patients with the Flt3/ITD compared with 74% for patients without this mutation (P = .005) (Table 3). The Kaplan-Meier estimate for event-free survival for patients with and without the Flt3/ITD was 7% and 44%, respectively (P = .002) (Figure 3). Overall survival for patients with the Flt3/ITD was 13% compared with 50% for patients without the Flt3/ITD (P = .02).
Prognostic factors were evaluated for overall and event-free
survival. We used univariate analysis to assess the prognostic significance of the Flt3/ITD, induction regimen, diagnostic WBC, cytogenetic class, and age. From the factors analyzed, only the presence of the Flt3/ITD was a significant prognostic marker for event-free and overall survival (Table
5). The hazard ratio for death and poor
outcome (death, induction failure, or relapse) in patients with the
Flt3/ITD compared with mutation-free patients was 2.1 (P = .03) and 2.6 (P = .002), respectively.
Multivariate analysis of the Flt3/ITD, induction regimen, and
diagnostic WBC showed that Flt3 mutation was the only independent
prognostic factor for overall and event-free survival
(P = .04 and .009, respectively) (Table
6).
We furthermore compared the Flt3/ITD distribution and outcome for these patients stratified by WBC at diagnosis. Four of the 38 patients (10%) with low WBC (WBC less than 20 000/µL) were positive for the Flt3/ITD compared with 11 of 53 patients (21%) with high WBC (more than 20 000/µL). Kaplan-Meier estimates for event-free survival at 8 years for patients with low WBC was 41% in Flt3/ITD-negative patients, and 0% for patients with the Flt3/ITD (P = .07). Kaplan-Meier estimate for event-free survival at 8 years for patients with high WBC was 46% for Flt3/ITD-negative patients, and 9% for patients with the Flt3/ITD (P = .009). We finally compared the clinical outcome of patients with and without Flt3/ITD on the basis of induction regimen. Of the study population, 76 patients were Flt3/ITD-negative, of which 53 received intensive and 23 received standard timing induction therapy. Event-free survival at 8 years for patients who received intensive timing therapy was 49% compared with 34% for patients who received standard timing induction regimen (P = .23). Of the 15 Flt3/ITD-positive patients, 7 received intensive timing and 8 received standard timing induction therapy. In the Flt3/ITD-positive patients, event-free survival at 8 years for patients who received intensive timing was 0% (0 of 7) compared with 12.5% (1 of 8) for the patients who received standard timing regimen (P = .37). Thus, patients with Flt3/ITD have a poor outcome, regardless of diagnostic WBC or induction regimen used.
We examined the prevalence and prognostic significance of the Flt3/ITD in pediatric patients with AML who were treated on a single treatment protocol. We demonstrated that a significant proportion (16.5%) of pediatric patients with AML who were treated on CCG-2891 had the Flt3/ITD mutation and that this mutation was a powerful, independent risk factor for poor outcome, regardless of diagnostic WBC or induction regimen used. Furthermore, we have shown that the Flt3/ITD is not a stem cell mutation and is restricted to the myeloid lineage. Previous studies showing association of this mutation with poor outcome in pediatric, adult, and elderly AML were limited by the fact that patients were not treated uniformly, making it difficult to assess the prognostic significance of this mutation. In our study, all patients were treated on the same treatment protocol (CCG-2891), and the population was a representative sample of the CCG-2891 population. Although median WBC and age at diagnosis for patients in the study were slightly higher than the median for the rest of the CCG-2891 patient population, this is most likely due to the fact that the marrow specimens available through the reference laboratory are enriched for older patient specimens and the ones with higher WBCs. Very young patients and patients with very low WBCs at diagnosis may have very few or no specimens available at the reference laboratory. This problem is inherent to the use of archived specimens and could be overcome by conducting a prospective study. Evaluation of the characteristics of the patients with the Flt3/ITD demonstrated the association of this mutation with leukocytosis. The Flt3/ITD has been shown to cause constitutive activation of the receptor tyrosine kinase,7 leading to autonomous, cytokine-independent cellular proliferation.8,12 Thus, the Flt3/ITD may be a causative factor for leukocytosis in patients who harbor this mutation. The mechanism by which this mutation leads to tyrosine kinase activation is unknown. Evaluation of the region of duplication has defined a general region of involvement within the JM domain coding region (exons 11 and 12). However, within this region, there is no common area of duplication shared by all patients. Deletions and point mutations in the JM coding domain of c-kit tyrosine kinase receptor gene have been reported that lead to constitutive activation of the c-kit receptor tyrosine kinase.21,22 In this case, it is the disruption of the JM domain of the receptor that allows ligand-independent receptor dimerization and receptor kinase activation. Thus, one may speculate that it is not a specific duplication that leads to the Flt3 receptor activation, but rather a conformational change of the JM domain of the Flt3 receptor, caused by the ITD, that leads to constitutive receptor dimerization and receptor tyrosine-kinase activation. Our study highlights the role of the Flt3/ITD as a predictor for poor outcome in pediatric AML. We have demonstrated that within a uniformly treated patient population, the Flt3/ITD is a powerful, independent prognostic factor, regardless of diagnostic WBCs, induction regimen, or cytogenetic markers. For example, 4 of the 15 study patients with the Flt3/ITD had favorable cytogenetics (inv 16, t[15;17] or t[8;21]), yet all died. This contrasts the 22 of 76 Flt3/ITD-negative patients with favorable cytogenetic markers who had an event-free survival of 64% at 8 years (14 of 22). Patients with the Flt3/ITD appear to be refractory to primary induction therapy, and for those who achieve remission, there is a high rate of relapse and death. Given the aggressive nature of the Flt3/ITD AML and the extremely poor outcome for these patients on current therapy, it may be appropriate to consider alternative therapies. Some patients with Flt3/ITD have had favorable outcome with allogeneic BMT. Of the 3 patients with Flt3/ITD who are alive in our series, 2 received unrelated bone marrow transplants after failing induction therapy. In a prior pediatric study, the lone survivor with Flt3/ITD had received an allogeneic bone marrow transplant.13 Thus, allogeneic stem cell transplantation as a postinduction therapy may improve outcome in this population. Patients without matched-related donors may benefit from unrelated stem cell transplants. For the significant number of patients with Flt3/ITD refractory to the primary induction therapy, or those with relapsed disease, more novel therapies such as tyrosine kinase inhibitors may prove useful. Constitutive activation of the Flt3 receptor tyrosine kinase may contribute to the pathogenesis of AML in the patients with Flt3/ITD. In chronic myelogenous leukemia (CML) in which constitutive activation of the c-abl kinase is responsible for CML leukemogenesis, inhibitors of tyrosine kinase have been successfully used for targeted therapy.23 Understanding the mechanism of action for Flt3/ITD and its role in leukemogenesis may eventually lead to the development of novel, targeted therapies for AML patients with Flt3/ITD.
Submitted July 6, 2000; accepted September 1, 2000.
Supported by NIH grants T32 CA09351, CA 18029, and ACS U10 CA13539.
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: Soheil Meshinchi, Fred Hutchinson Cancer Research Center, Clinical Research Division, D4-100, 1100 Fairview Ave N, Seattle, WA 98103; email: smeshinc{at}fhcrc.org.
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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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 T. Ikezoe, C. Nishioka, T. Tasaka, Y. Yang, N. Komatsu, K. Togitani, H. P. Koeffler, and H. Taguchi The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol. Cancer Ther., October 1, 2006; 5(10): 2522 - 2530. [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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D. Small FLT3 Mutations: Biology and Treatment Hematology, January 1, 2006; 2006(1): 178 - 184. [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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R. Grundler, C. Miething, C. Thiede, C. Peschel, and J. Duyster FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model Blood, June 15, 2005; 105(12): 4792 - 4799. [Abstract] [Full Text] [PDF]
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P. Brown, M. Levis, S. Shurtleff, D. Campana, J. Downing, and D. Small FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression Blood, January 15, 2005; 105(2): 812 - 820. [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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W. Tse, S. Meshinchi, T. A. Alonzo, D. L. Stirewalt, R. B. Gerbing, W. G. Woods, F. R. Appelbaum, and J. P. Radich Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia Blood, November 15, 2004; 104(10): 3058 - 3063. [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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I. J. Griswold, L. J. Shen, P. La Rosee, S. Demehri, M. C. Heinrich, R. M. Braziel, L. McGreevey, A. D. Haley, N. Giese, B. J. Druker, et al. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis Blood, November 1, 2004; 104(9): 2912 - 2918. [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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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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J. T. Barata, V. A. Boussiotis, J. A. Yunes, A. A. Ferrando, L. A. Moreau, J. P. Veiga, S. E. Sallan, A. T. Look, L. M. Nadler, and A. A. Cardoso IL-7-dependent human leukemia T-cell line as a valuable tool for drug discovery in T-ALL Blood, March 1, 2004; 103(5): 1891 - 1900. [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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T. Taketani, T. Taki, K. Sugita, Y. Furuichi, E. Ishii, R. Hanada, M. Tsuchida, K. Sugita, K. Ida, and Y. Hayashi FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy Blood, February 1, 2004; 103(3): 1085 - 1088. [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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A.-M. O'Farrell, J. M. Foran, W. Fiedler, H. Serve, R. L. Paquette, M. A. Cooper, H. A. Yuen, S. G. Louie, H. Kim, S. Nicholas, et al. An Innovative Phase I Clinical Study Demonstrates Inhibition of FLT3 Phosphorylation by SU11248 in Acute Myeloid Leukemia Patients Clin. Cancer Res., November 15, 2003; 9(15): 5465 - 5476. [Abstract] [Full Text] [PDF]
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 M. Bianchini, E. Ottaviani, T. Grafone, B. Giannini, S. Soverini, C. Terragna, M. Amabile, P. P. Piccaluga, M. Malagola, M. Rondoni, et al. Rapid Detection of Flt3 Mutations in Acute Myeloid Leukemia Patients by Denaturing HPLC Clin. Chem., October 1, 2003; 49(10): 1642 - 1650. [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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 K. Murata, H. Kumagai, T. Kawashima, K. Tamitsu, M. Irie, H. Nakajima, S. Suzu, M. Shibuya, S. Kamihira, T. Nosaka, et al. Selective Cytotoxic Mechanism of GTP-14564, a Novel Tyrosine Kinase Inhibitor in Leukemia Cells Expressing a Constitutively Active Fms-like Tyrosine Kinase 3 (FLT3) J. Biol. Chem., August 29, 2003; 278(35): 32892 - 32898. [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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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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H. Hackstein, T. Taner, A. F. Zahorchak, A. E. Morelli, A. J. Logar, A. Gessner, and A. W. Thomson Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo Blood, June 1, 2003; 101(11): 4457 - 4463. [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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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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S. Barjesteh van Waalwijk van Doorn-Khosrovani, C. Erpelinck, W. L. J. van Putten, P. J. M. Valk, S. van der Poel-van de Luytgaarde, R. Hack, R. Slater, E. M. E. Smit, H. B. Beverloo, G. Verhoef, et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients Blood, February 1, 2003; 101(3): 837 - 845. [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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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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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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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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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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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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L. M. Kelly, Q. Liu, J. L. Kutok, I. R. Williams, C. L. Boulton, and D. G. Gilliland FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model Blood, January 1, 2002; 99(1): 310 - 318. [Abstract] [Full Text] [PDF]
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S. P. Whitman, K. J. Archer, L. Feng, C. Baldus, B. Becknell, B. D. Carlson, A. J. Carroll, K. Mrozek, J. W. Vardiman, S. L. George, et al. Absence of the Wild-Type Allele Predicts Poor Prognosis in Adult de Novo Acute Myeloid Leukemia with Normal Cytogenetics and the Internal Tandem Duplication of FLT3: A Cancer and Leukemia Group B Study Cancer Res., October 1, 2001; 61(19): 7233 - 7239. [Abstract] [Full Text] [PDF]
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M. Levis, K.-F. Tse, B. D. Smith, E. Garrett, and D. Small A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations Blood, August 1, 2001; 98(3): 885 - 887. [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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Top
Abstract
Introduction
study population versus
CCG-2891
