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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Internal Medicine III and
Medical Informatics, University of Munich; Department of Internal
Medicine A, University of Muenster; Department of Internal Medicine I,
University of Cologne; Department of Oncology, Hematology and Tumor
Immunology, Robert-Rössle Cancer Center, Humboldt University,
Berlin; and Clinical Cooperative Group (CCG) Leukemia, Gesellschaft
für Strahlenforschung (GSF) National Research Center for
Environment and Health, Munich, Germany.
FLT3 length mutation (FLT3-LM) is a molecular marker potentially
useful for the characterization of acute myeloid leukemia (AML). To
evaluate the distribution of FLT3-LM within biologic subgroups, we
screened 1003 patients with AML at diagnosis for this mutation. FLT3-LM
was found in 234 (23.5%) of all patients and thus is the most frequent
mutation in AML described so far. Of all positive patients, 165 (70.5%) revealed a normal karyotype. Of the 69 patients with
chromosome aberrations, 24 (34.8%) had a t(15;17). The mutation was
rare in AML with t(8;21), inv(16) 11q23 rearrangements, and
complex karyotypes. FLT3-LM was not distributed equally within
different French-American-British (FAB) subtypes and was correlated
with a high peripheral blood count in FAB M1, M2, and M4
(P < .0001). In addition, the median age of patients
with the mutation was lower (54.9 vs 57.6 years;
P = .043), and, at a ratio of 1.36:1
(P = .023), the mutation was more frequent in females
than in males. Within the AMLCG study, FLT3-LM was of intermediate
prognostic significance. The complete remission rate of 70.3% in
patients with FLT3-LM was similar to that (70.4%) in patients without
FLT3-LM. Overall survival was not different between patients with or
without FLT3-LM. In contrast, patients with FLT3-LM had a significantly
shorter event-free survival (7.4 vs 12.6 months;
P = .0072) because of a higher relapse rate. Besides the
importance of FLT3-LM for biologic and clinical characterization of
AML, we show its value as a marker for disease monitoring based on 120 follow-up samples of 34 patients.
(Blood. 2002;100:59-66) The detection and characterization of chromosome
alterations in acute myeloid leukemia (AML) has provided the means to
identify distinct biologic and prognostic subgroups and to establish a new pathogenesis-oriented classification of the disease (World Health
Organization classification).1 Based on karyotype
analysis, 3 different groups of AML can be distinguished: (1) AML with
balanced chromosomal aberrations and favorable clinical course Thus, the main aims of this study were to analyze the frequency of
FLT3-LM in a large group of consecutive, unselected patients with AML;
to correlate FLT3-LM with karyotype, French-American-British (FAB)
subtype, and other biologic characteristics; to investigate the outcome
of patients with FLT3-LM in AML who entered the German AML Cooperative
Group (AMLCG) study and thus received standardized diagnostic work-up
and therapy; and to assess the applicability of this mutation as a
marker for minimal residual disease in follow-up studies.
Patient samples
Treatment protocol of the German AMLCG Study
Complete remission (CR) was assumed when there were less than 5% blasts in a normo-cellular bone marrow with normal levels of peripheral neutrophil and platelet counts. Overall survival (OS) was calculated from the first day of therapy to death. Disease-free survival (DFS) was measured from the date of CR to relapse or death. Cytogenetics Cytogenetic G-banding analysis was performed with standard methods. The definition of a cytogenetic clone and descriptions of karyotypes followed the International System for Human Cytogenetic Nomenclature.28Nucleic acid isolation DNA was extracted with a salting-out procedure29 from fresh bone marrow or peripheral blood cells after Ficoll separation of mononucleated cells. From the same specimens total RNA was isolated with RNeasy (Qiagen, Hilden, Germany) following the manufacturer's instructions.Genomic polymerase chain reaction One hundred nanograms genomic DNA was amplified specifically for exon 11 to exon 12, including intron 11, using primers 11F and 12R.30 Amplification was performed for 35 cycles (1 minute at 94°C, 1 minute at 60°C, 1 minute at 72°C), in 50 µL with 10 pmol each primer, 10 mmol dNTP, and 1.25 U Taq polymerase (Gibco/BRL, Eggenstein, Germany) in the buffer shipped by the supplier.Reverse transcription-polymerase chain reaction One microgram total RNA was reverse transcribed with 300 U Superscript (Gibco/BRL) in a 40-µL reaction using random hexamers as primers. An equivalent quantity of 25 ng RNA was amplified as described above.For each sample, ABL-specific reverse transcription-polymerase chain reaction (RT-PCR) was performed to control the integrity of DNA or RNA using primers abl5': 5'-GGCCAGTAGCATCTGACTTTG-3' and abl3': 5'-ATGGTACCAGGAGTGTTTCTCC-3'. Water instead of cDNA was included as a blank sample in each experiment. Amplification products were analyzed on 2% agarose gels stained with ethidium bromide. Semiquantitative analysis of the mutations Analysis of the amplification fragments on agarose gels revealed that the band representing the mutation was not always of the same intensity as the wild-type allele. Thus, we divided FLT3-LM into 5 categories according to densitometric estimations of ethidium bromide-stained agarose gels with the gelpro32-software (INTAS, Göttingen, Germany), as follows: (1) mutant fragment less intense than the wild-type band, (2) mutant fragment equally intense as the wild-type band, (3) mutant fragment more intense than the wild-type band, (4) only mutant fragment with loss of the wild-type band, and (5) presence of more than 1 mutant fragment (Figure 1C).
Sequencing All PCR products larger than the wild-type allele were sequenced to identify the type and extent of duplication. To this end, amplified fragments were cut from agarose gels and were isolated with Quiaex II (Qiagen) following the manufacturer's instructions. Approximately 100 ng purified PCR products were directly sequenced with 3.3 pmol primers as described above with the Big Dye Terminator Cycle Sequencing Kit (Perkin Elmer, Weiterstadt, Germany). After initial denaturation at 95°C for 5 minutes, 25 cycles at 94°C for 15 seconds and at 60°C for 4 minutes were performed. Sequence analysis was performed on an ABI 310 Sequence Detection System (Perkin Elmer).Statistical analysis Survival curves were calculated for OS, event-free survival (EFS), and DFS according to Kaplan-Meier.31 Survival curves were compared using a 2-sided log-rank test; results were considered significant at the P < .05 level on both sides. Pearson 2 analysis and Student t test
were used to test for differences in the distribution of dichotomous
variables and in the means of continuous distributions. Multivariate
analyses were performed for the respective dependent variables using
length mutations of the FLT3 gene, favorable cytogenetics,
unfavorable cytogenetics, and secondary etiology of AML as dichotomous
covariates, respectively, and age as a continuous covariate.
Genomic and RT-PCR of the FLT3 gene Genomic DNA and total RNA were obtained from the bone marrow of all 1003 patients at diagnosis. In addition, follow-up samples were obtained at 2 to 8 time points from 34 patients carrying the FLT3 mutation. Exons 11 to 12 of the FLT3 gene were amplified by genomic PCR, and exon 11 was amplified by RT-PCR. The FLT3-LM amplification yielded a higher molecular weight product on a 2% agarose gel stained with ethidium bromide (Figure 1). Of the 1003 samples analyzed, 234 (23.3%) revealed FLT3-LM. The sizes of the length mutation varied from 3 bp to more than 400 bp and comprised different parts of the juxtamembrane domain. In 70% of the samples, genomic and RT-PCR were performed in parallel. There were no discrepant results between the methods. In addition, there were no significant intensity variations when RT-PCR products were compared with genomic amplifications. Thus, transcription levels of wild-type and mutant FLT3 appeared to be in the same range.Correlation to cytogenetics Cytogenetic analyses were available from all 1003 analyzed patients. They were grouped into 9 categories according to cytogenetics: group 1, normal karyotype (n = 428); group 2, t(15;17) (n = 68); group 3, t(8;21) (n = 69); group 4, inv(16)/ t(16;16) (n = 47); group 5, t(Mq23) (n = 36); group 6, rare recurrent translocations t(6;9), t(1;3), inv(3)/t(3;3), t(3;12), t(3;21),
t(8;16) (n = 23); group 7, complex karyotypes (n = 120); group 8,  5/7/7q (n = 28); group 9, all others (n = 184). In the AMLCG
study, the different categories are defined as prognostically good
(groups 2, 3, and 4), intermediate (groups 1 and 9), and poor
(groups 7 and 8). Group 6 is a mixed group.
Ordinal
In total, FLT3-LM was more common in patients with de novo AML (24.5%)
than in patients with s-AML (15.6%) or in t-AML (11.5%) (Table
2). However, as in de novo
AML, FLT3-LM was highly correlated to normal and "other" karyotypes
in patients with s-AML and t-AML (Table 2).
The incidence of FLT3-LM according to karyotype was ranked as follows:
normal (38.6%) > t(15;17) (35.3%) > others (17.9%) > t(8;21) (8.7%) > rare recurrent translocations (4.3%) > complex karyotypes (3.7%) > Correlation with cytomorphology For 864 patients cytomorphologic analysis was available. No correlation with a single, specific FAB subtype was found (Table 3). Significant differences were found among the M3 and M5 subtypes with an FLT3-LM frequency of 23.4% for M3 versus 65% for M3v and of 6.4% for M5a versus 34.4% for M5b. The incidence of FLT3-LM was ranked as follows: M3v (65%) > M1 (36.1%) > M5b (34.4%) > M4 (26.8%) > M3 (23.4%) > M2 (19.6%) > M0 (17.2%) > M5a (6.4%). No patient was positive for the duplication in M4eo, M6, or M7. However, patients with M6 or M7 were encountered only as small groups (n = 17 and n = 10, respectively), and no definite conclusion is possible for these subtypes.
Correlation of FLT3-LM with leukocyte count in FAB subgroups For 810 patients, peripheral leukocyte counts at diagnosis were available. Among the total cohort, the leukocyte count was significantly higher in the group with the FLT3-LM than in the group without the mutation (P < .0001). When the leukocyte counts within single cytomorphologic subgroups were regarded, we found significantly elevated leukocyte counts only in FAB M1, M2, and M4 (Table 4).
Correlation of FLT3-LM with age and sex The median age of patients with FLT3-LM was 54.9 years versus 57.6 years in the group without the mutation (P = .043). As shown by2 analysis, the mutation was more frequent in
women than in men, with a 1.36:1 ratio (P = .023).
Prognostic significance of FLT3-LM within the German AMLCG study Analysis of the prognostic significance of FLT3-LM was restricted to 563 patients enrolled in the German AMLCG study. The median follow-up time was 11.1 months. Complete remission rates were similar between the groups with the mutation (70.3%) and without the mutation (70.4%). The group with FLT3-LM had a shorter OS than the group without the mutation (median, 12 months vs 15 months); however, this was not statistically significant (P = .3057) (Figure 2A). In contrast, EFS was significantly shorter in the group with the mutation (7.4 months vs 12.9 months) (P = .0072) (Figure 2C). In addition, patients with normal karyotype and other karyotypes (n = 360) were analyzed separately because they represent most of the mutation-positive patients and belong to the prognostically intermediate group. OS (11.5 months vs 12.1 months) was almost identical in both groups (Figure 2B), whereas EFS (7.3 months vs 9.4 months) was shorter in the group with the mutation (P = .0416) (Figure 2D). Disease-free survival was 8.4 versus 12.8 months (P = .0695) in the total group (Figure 2E) and 6.9 versus 9.0 months (P = .2408) in the intermediate group (Figure 2F). Multivariate analysis including cytogenetics, age, and secondary etiology of AML as covariates showed that the FLT3-LM state is not an independent prognostic factor for OS, EFS, or DFS.
Mutations at diagnosis and at relapse Twenty-five patients were analyzed at diagnosis and at relapse (Table 5). All patients with the mutation at diagnosis also carried it at relapse. Karyotype changes were found in 9 patients, 8 of whom had karyotype evolution. One patient experienced karyotype regression. All the chromosomal changes at relapse had to be interpreted as changes secondary to the FLT3 mutation because the FLT3 mutations were present in these patients before the chromosomal changes.
Semiquantitative analysis of the FLT3-LM Semiquantitative analysis of the amplified fragments representing the mutation in relation to the intensity of the wild-type allele was performed in 180 patients (Table 6). A definition of mutated fragments according to quantity is given in the "Materials and methods" section. In 60% of the patients studied at diagnosis, the mutated fragments are in the range of the wild-type allele (type 2). Ten percent of the patients have weak fragments, which may indicate that the mutation is present in only a part of the leukemic cells (type 1). Six percent revealed only the mutated allele type 4, and 11% are of type 3. Two to 4 different altered bands (different mutations) were found in 13% of the patients at diagnosis. At relapse only 16% had type 2 mutations, and types 1 and 5 mutations were never detected. In contrast, 84% revealed type 3 or type 4 mutations, indicating that there is a tendency to lose the wild-type allele during leukemic evolution. Loss of the wild-type allele was confirmed in 2 patients by fluorescence in situ hybridization (FISH) using a full-length cDNA clone (data not shown). Only one patient showed regression of the mutated allele to the wild-type allele. This patient also showed regression of the karyotype to a normal karyotype, which may be interpreted as a very early stage of relapse.
Evaluation of FLT3-LM as a follow-up marker So far, 120 peripheral blood and bone marrow samples of 34 patients with FLT3-LM were evaluated at 2 (12 patients), 3 (14 patients), 4 (1 patient), 6 (1 patient), 7 (2 patients), 8 (1 patient), and 9 (1 patient) time points during therapy. Some examples are summarized in Figure 3. Simple one-step PCR was performed with a sensitivity of 1/100 to 1/1000 cells, depending on the initial FLT3-LM/wild-type ratio. In 2 patients, FISH analysis could be done in parallel because of trisomy 8 at 4 and 8 time points, respectively. In one patient AML1-ETO-PCR and FISH analysis could be conducted because of an initial t(8;21) at 3 time points. Six patients had rare chromosome aberrations at diagnosis that were not detectable by PCR or FISH. Twenty-five patients had normal karyotypes at diagnosis; thus, in 31 patients FLT3-LM was the only marker available for follow-up studies. We found good accordance between FLT3-LM status and clinical state, cytomorphology, cytogenetics, FISH, and PCR. Based on FLT3-LM status, a relapse could be predicted in 4 patients before any other method 2 or 3 months before clinical relapse. These results suggest that FLT3-LM is a useful marker for follow-up studies.
According to cytogenetics, AML can be subdivided into certain prognostic subgroups. Because approximately 45% of all AML is cytogenetically normal and thus lacks markers that can be useful for subclassification and risk assessment, new molecular markers are urgently needed. We have analyzed the incidence of FLT3-LM in cytogenetic and cytomorphologic AML subgroups in great detail and have evaluated the prognostic significance within the German AMLCG study. The current study thus far comprises the largest series of patients in whom a systematic search for FLT3-LM has been performed and is the first one to assess FLT3-LM for distinct cytogenetic and cytomorphologic subgroups of AML. Its high frequency in patients without detectable cytogenetic aberrations or aberrations of currently unknown prognostic significance may provide the means to better understand the pathogenesis of these so far poorly characterized AML subgroups. The incidence of FLT3-LM in 23.3% of all unselected AML is in the range of that described before.12,13,21 FLT3-LM apparently is not independent of cytogenetics or of FAB subtype, as has been suggested by others.12,13,32 Incidence of FLT3-LM in different cytogenetic subgroups of AML We could show that FLT-LM is highly correlated with a normal karyotype. It is also relatively common with so-called other chromosome aberrations. The high incidence of FLT3-LM in the latter group may be considered a further hint that these other aberrations are secondary events.33 In all other cytogenetic groups FLT3-LM was rare. Thus, FLT3-LM may be a central principle that characterizes a large subgroup within the cytogenetically normal AML.Regarding the molecular mechanism of leukemogenesis, nonrandom
chromosomal translocations, which usually target and deregulate genes
coding for transcription factors and cause a differentiation block, are
thought to mediate the initiation of leukemia.3,4 In
addition, molecular mutations in the MLL, AML1,
and CEBP For reasons that are still unknown, AML with specific primary mutations
tends to accumulate certain secondary mutations. For example, AML with
t(8;21) tends to lose a sex chromosome, and with inv(16) it tends to
accumulate chromosome 21, 22, or both.37 Moreover, in a
subset of core-binding factor leukemia mutations within c-Kit, a
receptor tyrosine kinase that belongs to the same family as FLT3 has
been described.38 Now we have identified a mutation that
seems to occur most commonly in cytogenetically normal AML. We
speculate that at least one further mutation Incidence of the FLT3-LM in different cytomorphologic subgroups of AML FLT3-LM is not exclusively correlated with any certain FAB subtype, but it was not distributed equally within these groups. In addition, we found that FLT3-LM is specific for AML. Among 100 patients with acute lymphoid leukemia (ALL), we did not find a single patient with FLT3-LM (data not shown), confirming that FLT3-LM seems to be a rare event in ALL.2FLT3-LM and leukocytosis FLT3-LM has been associated with leukocytosis in acute promyelocytic leukemia.30 Because FLT3-LM has been shown to cause constitutive activation of the receptor tyrosine kinase,14 leading to autonomous, cytokine-independent cellular proliferation,16,22 it may be a causative factor for leukocytosis. Because FLT3-LM is particularly frequent in M3v, which is usually associated with elevated leukocyte counts, we speculate that FLT3-LM may be causative for the high leukocyte count in these patients. It still has to be analyzed whether those 35% of M3v patients in whom we did not detect FLT3-LM by PCR may carry a point mutation within the FLT3 gene, as has recently been shown to be a further common event in AML.19,20Prognostic significance of FLT3-LM The prognosis of AML depends on factors such as age, initial leukocyte count, FAB classification, karyotype, immune phenotype, and response to remission-induction therapy.39,40 Among them, cytogenetics is the most important prognostic factor.2 In most study groups, the good risk group is defined by t(15;17), t(8;21), and inv(16)/t(16;16); the intermediate group is defined by normal karyotypes and other chromosomal aberrations; and the poor risk group is defined by complex karyotypes,5/5q, 7/7q, 3q aberrations, and 11q23 translocations. Our study revealed that with the exception of
patients with t(15;17), nearly all patients with FLT3-LM belong to the
prognostically intermediate group, with a normal karyotype or
"other" chromosomal aberrations. Thus, we concentrated on the prognostic evaluation of 184 patients from the intermediate group with
normal cytogenetics and "other" aberrations. As could be shown in
the German AMLCG study, CR and OS rates of FLT3-LM-positive patients
did not differ significantly from those of FLT3-LM-negative patients.
EFS was worse (P = .0072) and DFS was slightly worse (P = .0695) in patients with FLT3-LM; both were consistent
with a higher relapse rate than in patients without the mutation.
Previously, a high significance of FLT3-LM as an indicator for a bad
prognosis has been shown in adults and in
children.21-24,41 This difference between our data and
findings from others may in part be an effect of a change in the
prognosis because of an intensification of induction therapy in the
AMLCG study. It could be speculated that double induction therapy with
at least one course of high-dose ara C may overcome the otherwise
poor prognosis of patients with FLT3-LM. Thus, within the AMLCG study,
patients with FLT3-LM were not classified as having high-risk AML
but were in the intermediate group.
In contrast to all AML patients, FLT3-LM has been shown not to correlate with prognosis in the AML M3 subgroup.30 Because of differentiation therapy with all-trans retinoic acid, the prognosis for AML M3 is favorable compared with other types of AML. Therefore, the M3/M3v group has to be analyzed separately. In our study of 68 patients with M3/M3v, it was not possible to compare the prognosis of the 24 patients with FLT-LM with those without the mutation, because death or relapses are too rare in the ongoing AMLCG trial to make these calculations reasonable.42 We found no reduced remission rates in our cohort of patients with the FLT3-LM, in contrast with findings of other studies.21,24 The slightly worse prognosis of patients carrying FLT3-LM within the AMLCG was not due to a reduced remission rate but to a significantly higher risk for relapse than in the group without the mutation. FLT3-LM at relapse Relapse is a major cause of treatment failure in AML, and relapsed leukemia is generally resistant to chemotherapy. Thus, relapse does not simply mean the reappearance of leukemia. More than half of the patients with relapsed AML had karyotype changes,43-45 frequently to a more complex karyotype and rarely to a normal or a clonally unrelated karyotype. These findings suggest that relapse is accompanied by clonal evolution. Few studies on molecular alterations are associated with relapse in AML. It may be speculated whether FLT3 mutations are responsible for disease progression and, therefore, are more common at relapse. We found the FLT3 mutation to be present at both time points in all 25 patients who could be analyzed at diagnosis and at relapse. This was in contrast to others, who described instability at diagnosis and relapse in 7 of 12 patients.46 In our study, 8 patients accumulated the mutation and 13 even proceeded to a hemizygous state of the mutation at relapse. This is in good agreement with the finding that the prognosis gets worse with an increasing ratio of FLT3-LM to the wild-type allele.47,48FLT3-LM as a follow-up marker Detection of minimal residual disease by highly sensitive PCR-based methods is of growing importance to monitor therapy responses and early relapses. However, only 25% of patients with AML carry fusion genes that are good targets for PCR detection. FLT3-LM now provides us with a PCR target for approximately another 20% of patients with AML. Because patients with FLT3-LM are prone to relapses, PCR detection of molecular relapses may be helpful in overcoming clinical relapse through early therapeutic intervention.Future perspectives Given the high relapse rates and the nature of the mutations characterized in the way it targets receptor tyrosine kinases, it may be appropriate to consider alternative therapies for FLT3-LM. Therefore, for patients with FLT3-LM who are refractory to primary induction therapy or for those with relapsed disease, novel strategies such as therapy with tyrosine kinase inhibitors may be useful. Hence, FLT3-LM may provide a novel molecular target for AML therapy.49This is to date the largest study on FLT3-LM in adult patients with AML. Based on our findings, we conclude that FLT3-LM is most frequent in the subgroup with normal karyotypes. Thus, with the growing importance of minimal residual disease studies in AML, FLT3-LM provides a molecular marker in a large subset of patients with AML in whom no molecular monitoring was possible until now. Because therapy outcomes for patients with and without FLT3-LM did not differ significantly in our investigation, the prognostic significance of FLT3-LM in adult AML should be further evaluated before FLT3-LM is used as a possible marker for up-front risk stratification in adult AML.
We thank Gudrun Mellert and Sabine Koneberg for excellent technical assistance.
Submitted July 25, 2001; accepted February 28, 2002.
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.
Presented in part at the 42nd annual meeting of the American Society of Hematology, December 1-5, 2000, San Francisco, CA (abstract 3569). Reprints: Susanne Schnittger, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany; e-mail: susanne.schnittger{at}med3.med.uni-muenchen.de.
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F. Dicker, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia Blood, August 15, 2007; 110(4): 1308 - 1316. [Abstract] [Full Text] [PDF]
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S. Schnittger, C. Schoch, W. Kern, C. Mecucci, C. Tschulik, M. F. Martelli, T. Haferlach, W. Hiddemann, and B. Falini Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype Blood, December 1, 2005; 106(12): 3733 - 3739. [Abstract] [Full Text] [PDF]
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R. E. Gale, R. Hills, A. R. Pizzey, P. D. Kottaridis, D. Swirsky, A. F. Gilkes, E. Nugent, K. I. Mills, K. Wheatley, E. Solomon, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia Blood, December 1, 2005; 106(12): 3768 - 3776. [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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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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M. S. Tallman, D. G. Gilliland, and J. M. Rowe Drug therapy for acute myeloid leukemia Blood, August 15, 2005; 106(4): 1154 - 1163. [Abstract] [Full Text] [PDF]
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T. Haferlach, A. Kohlmann, S. Schnittger, M. Dugas, W. Hiddemann, W. Kern, and C. Schoch Global approach to the diagnosis of leukemia using gene expression profiling Blood, August 15, 2005; 106(4): 1189 - 1198. [Abstract] [Full Text] [PDF]
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D. E. Lopes de Menezes, J. Peng, E. N. Garrett, S. G. Louie, S. H. Lee, M. Wiesmann, Y. Tang, L. Shephard, C. Goldbeck, Y. Oei, et al. CHIR-258: A Potent Inhibitor of FLT3 Kinase in Experimental Tumor Xenograft Models of Human Acute Myelogenous Leukemia Clin. Cancer Res., July 15, 2005; 11(14): 5281 - 5291. [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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C. Choudhary, J. Schwable, C. Brandts, L. Tickenbrock, B. Sargin, T. Kindler, T. Fischer, W. E. Berdel, C. Muller-Tidow, and H. Serve AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations Blood, July 1, 2005; 106(1): 265 - 273. [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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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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W. Fiedler, H. Serve, H. Dohner, M. Schwittay, O. G. Ottmann, A.-M. O'Farrell, C. L. Bello, R. Allred, W. C. Manning, J. M. Cherrington, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease Blood, February 1, 2005; 105(3): 986 - 993. [Abstract] [Full Text] [PDF]
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B. Falini, C. Mecucci, E. Tiacci, M. Alcalay, R. Rosati, L. Pasqualucci, R. La Starza, D. Diverio, E. Colombo, A. Santucci, et al. Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype N. Engl. J. Med., January 20, 2005; 352(3): 254 - 266. [Abstract] [Full Text] [PDF]
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K. K. Ballen and R. P. Hasserjian Case 2-2005 - A 39-Year-Old Woman with Headache, Stiff Neck, and Photophobia N. Engl. J. Med., January 20, 2005; 352(3): 274 - 283. [Full Text] [PDF]
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M. S. Tallman New Strategies for the Treatment of Acute Myeloid Leukemia Including Antibodies and Other Novel Agents Hematology, January 1, 2005; 2005(1): 143 - 150. [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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R. M. Stone, D. J. DeAngelo, V. Klimek, I. Galinsky, E. Estey, S. D. Nimer, W. Grandin, D. Lebwohl, Y. Wang, P. Cohen, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412 Blood, January 1, 2005; 105(1): 54 - 60. [Abstract] [Full Text] [PDF]
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T. Kindler, F. Breitenbuecher, S. Kasper, E. Estey, F. Giles, E. Feldman, G. Ehninger, G. Schiller, V. Klimek, S. D. Nimer, et al. Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML) Blood, January 1, 2005; 105(1): 335 - 340. [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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W. Kern, D. Voskova, C. Schoch, W. Hiddemann, S. Schnittger, and T. Haferlach Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia Blood, November 15, 2004; 104(10): 3078 - 3085. [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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J. Jiang, J. G. Paez, J. C. Lee, R. Bo, R. M. Stone, D. J. DeAngelo, I. Galinsky, B. M. Wolpin, A. Jonasova, P. Herman, et al. Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML Blood, September 15, 2004; 104(6): 1855 - 1858. [Abstract] [Full Text] [PDF]
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S. Takahashi, M. J. McConnell, H. Harigae, M. Kaku, T. Sasaki, A. M. Melnick, and J. D. Licht The Flt3 internal tandem duplication mutant inhibits the function of transcriptional repressors by blocking interactions with SMRT Blood, June 15, 2004; 103(12): 4650 - 4658. [Abstract] [Full Text] [PDF]
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P. George, P. Bali, P. Cohen, J. Tao, F. Guo, C. Sigua, A. Vishvanath, W. Fiskus, A. Scuto, S. Annavarapu, et al. Cotreatment with 17-Allylamino-Demethoxygeldanamycin and FLT-3 Kinase Inhibitor PKC412 Is Highly Effective against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3 Cancer Res., May 15, 2004; 64(10): 3645 - 3652. [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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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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C. Muller-Tidow, J. Schwable, B. Steffen, N. Tidow, B. Brandt, K. Becker, E. Schulze-Bahr, H. Halfter, U. Vogt, R. Metzger, et al. High-Throughput Analysis of Genome-Wide Receptor Tyrosine Kinase Expression in Human Cancers Identifies Potential Novel Drug Targets Clin. Cancer Res., February 15, 2004; 10(4): 1241 - 1249. [Abstract] [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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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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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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M. Libura, V. Asnafi, A. Tu, E. Delabesse, I. Tigaud, F. Cymbalista, A. Bennaceur-Griscelli, P. Villarese, G. Solbu, A. Hagemeijer, et al. FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress Blood, September 15, 2003; 102(6): 2198 - 2204. [Abstract] [Full Text] [PDF]
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 M. W. N. Deininger and B. J. Druker Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib Pharmacol. Rev., September 1, 2003; 55(3): 401 - 423. [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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T. Haferlach, W. Kern, C. Schoch, W. Hiddemann, and M. C. Sauerland In Reply: J. Clin. Oncol., August 1, 2003; 21(15): 3004 - 3005. [Full Text] [PDF]
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J. Delaunay, N. Vey, T. Leblanc, P. Fenaux, F. Rigal-Huguet, F. Witz, T. Lamy, A. Auvrignon, D. Blaise, A. Pigneux, et al. Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup Blood, July 15, 2003; 102(2): 462 - 469. [Abstract] [Full Text] [PDF]
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 V. T. Phan, D. B. Shultz, B.-T. H. Truong, T. J. Blake, A. L. Brown, T. J. Gonda, M. M. Le Beau, and S. C. Kogan Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation Mol. Cell. Biol., July 1, 2003; 23(13): 4573 - 4585. [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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Top
Abstract
Introduction
genes have been described in
AML.