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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Medizinische Klinik und Poliklinik I,
Universitätsklinikum Carl Gustav Carus der Technischen
Universität, Dresden; and the Abteilung Hämatologie,
Onkologie und Immunologie, Philipps Universität Marburg, Germany.
Constitutive activation of the FLT3 receptor tyrosine kinase,
either by internal tandem duplication (ITD) of the juxtamembrane region
or by point mutations in the second tyrosine kinase domain (TKD), has
been described in patients with acute myelogenous leukemia (AML). We
analyzed the prevalence and the potential prognostic impact of FLT3
mutations in 979 AML patients. Results were correlated with cytogenetic
data and the clinical response. FLT3-ITD mutations were found in 20.4%
and FLT3-TKD mutations in 7.7% of the patients. Each mutation was
associated with similar clinical characteristics and was more prevalent
in patients with normal karyotype. Significantly more FLT3 aberrations
were found in patients with FAB M5, and fewer were found in patients
with FAB M2 and M6. Although less frequent in patients with cytogenetic
aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17)
and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele
on the DNA level was heterogeneous, ranging from faint mutant bands in
some patients to predominant mutant bands in others. Based on
quantitative analysis, the mutant-wild-type (wt) ratio ranged from
0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie,
greater than 0.78) had significantly shorter overall and disease-free
survival, whereas survival in patients with ratios below 0.78 did not
differ from those without FLT3 aberrations. Multivariate analysis
confirmed a high mutant/wt ratio to be a strong independent prognostic
factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be
associated with monocytoid differentiation. A high mutant/wt ratio in
ITD-positive patients appears to have a major impact on the prognostic relevance.
(Blood. 2002;99:4326-4335) Acute myelogenous leukemia (AML) describes a group
of hematopoietic stem cell malignancies, affecting approximately 2 to 3 adults per 100 000 each year in Western countries. Cytogenetic aberrations represent one of the most important independent prognostic factors. Several studies have shown that good-risk cytogenetics, such
as t(8;21), are associated with significantly better survival than
poor-risk chromosomal aberrations, such as monosomy 7 or monosomy 5 (reviewed in Lowenberg et al1). Novel treatment strategies
take into account these prognostic factors to develop risk-stratified
treatment options. The ultimate goal is to offer more intensive
treatment options The growth and differentiation of hematopoietic cells is governed by
the concerted action of growth factors and their receptors. One of
these receptors, FMS-like tyrosine kinase 3 (FLT3),3 also
called stem cell kinase 1 (STK1)4 or fetal liver kinase 2 (flk2),5 belongs to the group of class 3 receptor tyrosine kinases, together with other growth factor receptors such as c-Kit, PDGF-R, and c-fms (for review, see Shurin et
al6). The FLT3 protein is expressed on early hematopoietic
and lymphoid progenitors4,7 and seems to play an important
role in early stem cell survival and myeloid
differentiation.6 The protein is highly expressed in most
patients with AML and in up to 50% of leukemic blasts in patients with
acute lymphoblastic leukemia (ALL).7-11
Recently, internal tandem duplication (ITD) mutations of the
FLT3 gene have been described in approximately 20% of
patients with adult AML12-16; a lower incidence
(5%-16.5%) has been reported in childhood leukemia.17-19
These mutations cluster in exons 11 and 12 of the human FLT3
gene on chromosome 13q12, a part that codes for the juxtamembrane
domain of the FLT3 protein. Mutations typically consist of an in-frame
inserted sequence corresponding to the region between amino acids (AA)
575 and 613 of the FLT3 protein.20 This alteration induces
constitutive activation of the protein20 and leads to
activation of downstream signal molecules, including STAT5, Ras, and
MAP kinase, when transfected into 32D or BA/F3 cells.21,22
In AML patients, the FLT3-ITD mutations were found to be associated
with increased leukocyte counts and were frequent in patients lacking
other cytogenetic aberrations. The presence of FLT3 aberrations appears
to be associated with an unfavorable clinical
response.14-16,23 However, most studies published so far
are limited in patient number, and patients were not treated according
to a single protocol, which renders an assessment of the potential
prognostic impact of this mutation difficult. More recently, point
mutations in codon 835 of the FLT3 gene have been described
in approximately 7% of patients with AML.24 These mutations are located in the activation loop of the second tyrosine kinase domain (TKD) of FLT3 and constitutively activate the
protein.24 The prognostic relevance of this alteration is
not yet defined. The aims of the present study were to characterize the
incidence of FLT3-ITDs and FLT3-TKD mutations in a large (n = 979),
unselected, and well-characterized cohort of patients with AML and to
study the potential prognostic impact of these alterations in patients treated on a single protocol. Finally, we addressed the origin and the
prognostic relevance of differences in the prevalence of mutant and
wild-type (wt) FLT3-ITD alleles.
Patients
In patients younger than 60, first induction therapy consisted of
triple therapy with 10 mg/m2 mitoxantrone (days
4-8), 100 mg/m2 cytosine arabinoside (ara-C) (days
1-8), and 100 mg/m2 VP16 (days 4-8) (MAV). Second induction
consisted of 2 × 1000 mg/m2 ara-C (days 1-5) and 100 mg/m2 m-AMSA (days 1-5) (MAMAC). Patients at intermediate
cytogenetic risk were referred for allogeneic hematopoietic stem cell
transplantation (HSCT) from an HLA-identical sibling donor. Patients at
intermediate cytogenetic risk without a sibling donor and patients at
low risk were randomized to receive intermediate dose ara-C
(2 × 1000 mg/m2 every 12 hours days 1-6) (I-MAC) or
high-dose ara-C (2 × 3000 mg/m2 every 12 hours days 1-6)
(H-MAC) plus mitoxantrone (10 mg/m2 days 4-6), which was
followed by autologous peripheral blood SCT (intermediate cytogenetic
risk) or MAMAC (low cytogenetic risk). Patients at high cytogenetic
risk were referred for allogeneic HSCT, including the option of
unrelated HSCT. Patients without a donor were treated with either I-MAC
or H-MAC and were referred for autologous peripheral blood SCT.
Patients older than 60 received 2 induction cycles containing 45 mg/m2 daunorubicin (days 3-5) and 100 mg/m2
ara-C (days 1-7) (DA). Postremission therapy consisted of MAMAC.
Complete remission (CR) was defined as the presence of less than 5%
blasts cells in a standardized bone marrow aspirate after the second
course of induction. Only patients with a fully regenerated peripheral
blood count were considered to be in CR.
This study was approved by the ethics board of the Technical University
Dresden. Each patient gave written informed consent to participate in
the study.
Patient samples
Polymerase chain reaction for exons 11 and 12 Polymerase chain reaction (PCR) was performed on genomic DNA using published primer molecules.14 In brief, 1 µL DNA was amplified in a volume of 50 µL containing 50 mM KCl, 10 mM Tris-HCl, pH 8.3, 1.5 mM MgCl2, 0.001% (wt/vol) gelatin, 200 µM dNTPs, oligonucleotides (FLT3-11F and FLT3-12R; 0.5 µM each), and 1 U Taq DNA-polymerase (Perkin-Elmer, Norwalk, CT). The PCR consisted of an initial incubation step at 94°C for 150 seconds followed by 35 cycles at 94°C for 30 seconds, 57°C for 60 seconds, and 72°C for 120 seconds, and a final elongation step at 94°C for 30 seconds and 60°C for 10 minutes. PCR products were analyzed on standard 3% agarose gels. Reverse transcriptase (RT)-PCR was performed for those 38 samples for which no DNA was available. The RT reaction was performed as outlined recently.29 In brief, 1 µg total RNA was reverse transcribed using 200 U M-MLV RT (Superscript; Gibco BRL, Karlsruhe, Germany), in the presence of 40 U RNAse-inhibitor (RNAsin; Promega, Mannheim, Germany) in a total volume of 20 µL. One microliter of the RT reaction was used for PCR.PCR for exon 17 and RFLP analysis PCR for the detection of mutations in codon 835/836 was performed using published primer molecules.24 The conditions were identical to those mentioned above; however, hot start was performed using AmpliTaq Gold DNA polymerase (Perkin-Elmer). Five microliters PCR product was mixed with 5 µL restriction mix containing 5 U EcoRV (New England Biolabs, Frankfurt, Germany) in 1× Buffer 3 and was digested for 1 hour at 37°C. Agarose gel electrophoresis was performed as described above.Genescan analysis of the mutant to wild-type FLT3-ITD ratio For Genescan analysis, PCR primer FLT3 11F14 was labeled with 6-FAM (TIB MOLBIOL, Berlin, Germany). PCR setup was identical to the standard PCR; however, AmpliTaq Gold DNA-polymerase (1 U; Perkin-Elmer) was used. PCR conditions were modified as follows: preincubation at 95°C for 11 minutes, followed by 30 seconds at 94°C, 30 seconds at 57°C, and 60 seconds at 72°C. The total number of cycles was 27. Quantitative addition of +A overhangs of all PCR molecules30 was achieved using a final elongation step with 60°C for 45 minutes. The DNA concentration was determined and adjusted to 5 ng. Precautions taken to achieve reproducible results and the conditions of the Genescan analysis have been described recently.31 Several parameters were tested for their influence on the quantitative results. Among these, the DNA concentration was particularly important (see above). Experiments using dilutions of cloned ITD-fragments with different sizes (18-111 bp) showed no effect of the size of the ITD on the quantitative result (data not shown). We analyzed DNA from the peripheral blood of 50 healthy persons using this technique and did not find any evidence for the presence of additional FLT3 signals.PCR assay for the detection of allelic loss at 13q12 The principal basis of this assay has been described.32,33 The relative amplification of the FLT3 exon 11/12 region was compared to the genomic amplification of the human growth hormone gene (HGH), located on chromosome 17q22-24.34 Primers for HGH were as described recently35; primer HGH-s was labeled with HEX. PCR conditions were identical to those described for the analysis of the mutant/wt ratio (see above). DNA from 22 healthy persons and 12 AML patients with an FLT3 mutant/wt allelic ratio greater than 2 was analyzed. To assess the ability of this assay to measure an increase in FLT3 genomic equivalents, BAC (1-3 pg) DNA (see below) was added to a DNA sample of a healthy person, showing a linear increase with the added amount of BAC 85P08.Sequence analysis For sequence analysis of the FLT3-ITD mutations, DNA showing additional bands was amplified in a second reaction. PCR products were separated on 3% agarose gels, and the mutant bands were isolated and cloned into pCR 2.1 TOPO vectors (Invitrogen, Leek, The Netherlands). After the preparation of plasmid DNA, samples were sequenced using Big Dye Terminator cycle sequencing chemistry (ABI). Sequences were compared to the wild-type sequence (accession no. E970630). For analysis of the FLT3-TKD mutations, digested PCR products were separated electrophoretically, and the undigested bands were isolated as described above. The resultant DNA was used for direct cycle sequencing. If this approach did not yield sufficient data, EcoRV digestion was performed, and the undigested fragments were cloned and sequenced as described above.Fluorescence in situ hybridization Fifty different bacterial artificial chromosome (BAC) clones (RPCI-11 human male BAC library; BACPAC Resources, Oakland, CA) containing DNA from the chromosomal region 13q12 were selected and screened for the presence of the FLT3 gene by PCR. BAC-DNA was isolated from clone 85P08 (Qiagen Large-Construct Kit; Qiagen) and was labeled by nick translation (Vysis, Downers Grove, IL) with fluorophore-labeled dUTP (SpectrumRed; Vysis). For each fluorescence in situ hybridization (FISH) experiment, 200 ng probe mixed with 1 µg COT-1 DNA (Boehringer Mannheim, Germany) and 2 µg herring sperm DNA (Boehringer Mannheim) were applied per target area. FISH was performed as outlined recently.36 A second probe (LSI 13, 13q14, SpectrumGreen, Vysis) was included in the analysis.Statistical analysis Using the Kaplan-Meier method, OS and DFS were calculated only for those patients who had been included in the SHG AML-96 study.37 Cox regression analysis was performed to calculate the relative risk of patients with high FLT3 ratios. Comparisons between different groups were made using 2-sided Fisher exact test (dichotomic variables) or the nonparametric Mann-Whitney U test (continuous variables). P < .05 was considered significant. For multivariate analysis of prognostic factors, a proportional hazard regression model was used. Stepwise forward selection was performed. Variables were added at P < .01 and were deleted at P > .05. All calculations were performed using the SPSS software package, version 4.1 (SPSS, Chicago, IL).
We have analyzed samples from 979 patients with newly diagnosed AML and 34 patients with transformed MDS (RAEB-t) for the presence of ITDs and for mutations in the second tyrosine kinase domain (TKD; codons 835/836) of the FLT3 gene. An ITD was found in 200 of 979 (20.4%) AML patients and in 3 of 34 (8.8%) patients with RAEB-t. A mutation in the TKD was present in 75 of 979 (7.7%) patients with AML and in 2 of 34 (5.9%) patients with MDS. Seventeen AML patients had an FLT3-ITD and a mutation in the TKD. Thus, 258 of 979 (26.4%) AML patients had activation of FLT3, and 5 of 34 (14.7%) with transformed MDS. The presence of any type of FLT3 mutation was significantly associated
with absolute leukocyte counts and bone marrow blast counts (Table
1). No association was seen between
patient age at diagnosis and the prevalence of FLT3 mutations (Figure
1A). Compared with the overall incidence,
the frequency of FLT3 mutations with respect to French-American-British
(FAB) subtype was significantly lower in patients with M2 and M6
morphologies and was increased in patients with M5a and M5b (Figure
1B).
Correlation of cytogenetic data with the FLT3-ITD and TKD mutations is
shown in Table 2. Most FLT3-ITD mutations
were observed in patients with normal karyotype as assessed by standard
cytogenetics (134 of 415 with 46,XX or 46,XY compared to 44 of 445 with
cytogenetic aberrations; P < .0001). Likewise, FLT3-TKD
mutations were also significantly more frequent in patients with normal
karyotype (50 of 415) than in those with cytogenetic aberrations (23 of 445) (P = .0003). A significantly higher prevalence of
FLT3-ITD mutations was found in patients with t(15;17) (31%;
P < .0001), and in patients with TKD mutations there was
a trend for a significantly higher prevalence (19%,
P = .056). The highest proportion of FLT3-ITDs was
observed in patients carrying the t(6;9)/DEK-CAN fusion
DNA sequence analysis of FLT3-ITDs was performed in 97 patients, in whom 101 sequences were identified. In 93 patients a single sequence was found, and 4 patients displayed 2 different mutant FLT3-sequences. All fragments contained in-frame rearrangements; the median length of the inserted sequence was 54 bases (range, 6-180 bases). The ITD sequences included sequences from AA573 to AA620 of the FLT3 protein, thus the vast majority of mutations contained sequences from exon 11. A major cluster was seen for the stretch between codons 591 and 601, which was present in 60% of the ITDs. In 3 patients, sequences derived from intron 11 were identified in the inserted segment. Additional bases not matching FLT3 sequences were found in 45 of 101 FLT3-ITDs (45%), and in 2 patients the lengthened FLT3-PCR products contained 18 and 24 bases not related to FLT3 sequences. Examples of the FLT3 exon 17 mutations are shown in Figure 2C.
Confirmation of mutations by sequence analysis was performed in all 77 patients who had been identified by RFLP-screening. Eighty-seven
mutations were found; 8 samples contained 2 different mutations, and 1 sample contained 3 different mutations (Table 3). Transversion mutations of the first
position of codon 835, either G-T or G-C, leading to amino acid
exchanges from aspartic acid to tyrosine or histidine respectively,
were the most common alterations, accounting for 52 of 87 mutations
(60%). In contrast to these single-base exchanges, in 13 patient
samples a complete deletion of codon 836 was identified. Two patient
samples contained insertion mutations: one 3 bases, coding for
arginine, the other sample contained a complex change with the
amino acids leucine and lysine inserted after codon 835 in combination
with a point mutation, changing isoleucine to serine in codon 836. None
of the changes found altered the reading frame. In 10 of the 17 patients with an FLT3-ITD mutation and an FLT3-TKD mutation, analysis
could be performed on the distribution of both mutations between the 2 copies of the FLT3 gene using PCR for exons 11 to 17 on cDNA material. Six of these patients showed a TKD mutation of the wt allele,
whereas in 4 patients the analysis indicated the presence of the TKD
mutation on the allele carrying the ITD mutation (data not shown).
Missing or very weak amplification of the genomic FLT3 wt alleles was observed in a subgroup of patients with FLT3-ITDs on standard agarose gels (Figure 2A). This finding led us to study this phenomenon in more detail. First, a quantitative assay based on Genescan analysis was developed. This assay compares the relative abundance of wt and mutant FLT3 alleles. Genomic DNA from 121 patients with FLT3-ITD was analyzed. The ratio of mutant to wt FLT3 ranged from 0.03 to 32.56, with a median of 0.78. Repeated analysis in 42 patients gave almost identical results (median deviation, 0.04). Twenty (16.5%) patients were found to harbor more than one FLT3 mutant allele, and the median was 2 mutant alleles (range, 2-5). Fragments of corresponding length were detected using cloning and sequence analysis in 4 of these patients. In 16 patients, the FLT3 mutant/wt ratio exceeded 2; thus the intensity of the wt allele was half or less of the intensity of the mutant allele (Figure 2D). This might indicate a loss of the wt allele in these patients. To analyze this phenomenon in more detail, we performed FISH. Metaphase
preparations of 9 patients with FLT3-ITD showing a strong
overrepresentation of the mutant allele (ie, mutant/wt ratio greater
than 2) were screened for chromosomal loss at 13q12 using a BAC clone,
which contained the FLT3 genomic region. None of these
samples displayed loss of the FLT3 locus at 13q12 (Figure 3A). To exclude a deletion of only the
FLT3 gene, a probe corresponding to the cDNA sequence was
used that yielded ambiguous results because of low signal intensity. To
clarify this, we used a PCR-based assay comparing the relative genomic
amplification of FLT3 and the human growth hormone gene,
HGH, a single copy gene localized on chromosome 17. The
results are summarized in Figure 3B. We did not find any difference in
the FLT3/HGH allelic ratio between healthy persons (n = 22) and
patients with a mutant/wt FLT3 allelic ratio greater than 2 (n = 12).
In contrast, we were able to demonstrate such a difference in a patient
with monosomy 13 proven by conventional and spectral karyotyping
analysis. This might indicate that the observed loss of the wt-FLT3
allele was not due to allelic deletion but to the consequence of
homologous recombination.
First, we correlated the presence of the different types of FLT3
mutations (ITD, TKD, or ITD+TKD) with the clinical outcome in 640 patients treated in the AML SHG96 trial between 1996 and April 2000. Patients with AML-M3 were analyzed separately because they had been
treated according to a different protocol (APL 199326). Patients treated by SCT were censored at the time of transplantation to
eliminate the potential bias induced by this intensified treatment. Detection of an FLT3 aberration had no influence on the remission rate
(CR rate in patients with de novo AML younger than 60, intermediate risk cytogenetics, FLT3-ITD negative, 66.8% (n = 217); in patients with FLT3-ITDs, 71.2% (n = 66). As shown in Figure
4A-D, the presence of an FLT3-ITD or a
TKD mutation was associated with inferior OS and DFS for the entire
group and for the group of patients younger than 60 with de novo
AML/RAEB-t and intermediate-risk cytogenetics. However, these
differences were statistically significant only for the DFS in patients
with ITD mutations and the OS in young patients with TKD mutations. No
significant difference was seen in patients with both types of
mutations; however, this may be a result of the small sample size. The
presence of an FLT3-ITD mutation was associated with a statistically
increased risk for relapse (Figure 5A).
The patient with t(8;21) and FLT3-ITD is still in remission after 24 months. In addition, in the group of patients at poor risk, no difference was observed between FLT3-ITD- and TKD-positive and -negative patients in either OS or DFS. No significant difference was seen in the OS and DFS between patients with FLT3-ITD and those without this aberration in patients with t(15;17). We next analyzed the impact of the FLT3 mutant/wt ratio. Patients
were grouped according to a FLT3 ratio below or above the median of
0.78 (Figure 6A). As shown in Figure 6
for the DFS in patients with AML who were younger than 60 years and had
intermediate-risk cytogenetics, we observed highly significant shorter
OS and DFS in patients with ratios above the median than in patients
with ratios below this value and compared with FLT3-ITD patients
(Figure 6B-C). No significant difference in OS and DFS was observed
between the latter 2 groups. The probability of relapse was
significantly increased in these patients (Figure 5B). Cox regression
analysis showed a relative risk of relapse of 1.6 (95% confidence
interval, 1.204-2.169; P = .001) in patients whose
mutant/wt ratio was greater than 0.78 compared with patients without
FLT3 aberrations. To further characterize these risk groups, we also
looked for patients whose ratio was below the 25th
percentile (ratio
We also compared the clinical variables in the different groups. Patients with high mutant/wt ratios were found to have significantly higher WBC and BM blast counts than patients with low ratios, but these groups did not differ significantly with respect to age, FAB subtype, or karyotype characteristics. Multivariate analysis was performed to investigate whether FLT3
aberrations represented an independent prognostic factor. We included
several known risk factors in the model (age, cytogenetics, WBC, sAML)
and FLT3 aberrations (ITD, TKD, and ITD+TKD mutations) and the FLT3-ITD
ratio. As shown in Table 4, though FLT3
mutations were not associated with OS and DFS on multivariate analysis, a high mutant/wt ratio was found to represent an independent prognostic factor with odds ratios between 1.8 and 8.
We have analyzed the frequency of FLT3 gene mutations in 979 patients with AML. The overall incidence of FLT3 tandem mutations was 20.4% (200 of 979), which is consistent with numbers reported by other groups.12 In the same cohort of patients, point mutations of the activation loop of the second tyrosine kinase domain (AA 835/836) were identified in 7.7% (75 of 979). Taken together, constitutive activation of FLT3 was present in 26.4% (258 of 979) of these patients, which indicates that FLT3 is an important target of mutational activation in adult AML. Comparison of FLT3 mutational data and the clinical and cytogenetic
findings revealed several parallels between the 2 types of mutation.
FLT3-ITD and TKD mutations were associated with similar clinical
features Our results on the prognostic relevance are in line with other reports14-16 showing that the presence of an FLT3-ITD mutation is associated with worse clinical response. However, the prognostic impact of FLT3-ITDs in our study was less pronounced than in other reports and reached statistical significance only for DFS. Several factors might be responsible for this observation. The overall follow-up time in our study is only 12.2 months (range, 0-60.3 months). Because autologous or allogeneic SCT could influence the outcome, patients treated with transplantation were censored at the time of transplantation, which further shortened the follow-up time. The fact that 140 patients underwent transplantation might affect the analysis because these patients are not eligible for the long-term outcome. Differences might also be attributed to the assessment of FLT3-ITDs. In
the present study, we regarded any additional FLT3 signal as ITD+.
However, using a quantitative assay based on Genescan analysis after
PCR with fluorescently labeled primers, we found considerable
heterogeneity of the mutant/wt ratio in 121 FLT3-ITD+ patients
analyzed, with a median ratio of 0.78 (range, 0.03 to 32.56). When we
looked for the prognostic relevance of this ratio, we saw that a high
ratio of the ITD allele compared to the wt allele conferred a negative
prognostic impact with respect to OS and DFS (Figure 6). However,
because of our results, the poor outcome was not confined to patients
with clear loss of the wt allele, which was already visible on standard
agarose gels, but appeared to increase dramatically when the ratio of
the mutant/wt FLT3 exceeded 1. These patients had a significantly
increased rate of relapse; even more important, recurrent disease
developed rapidly, with a median OS time of 8 months in patients
otherwise considered at intermediate risk. Multivariate analysis showed that a high mutant/wt ratio was an independent prognostic factor for
worse OS and DFS (Table 4). In contrast, as shown in Figure 6, patients
with low allelic ratios did not have significantly different OS and DFS
than patients without FLT3-ITD mutations. When other groups were
chosen In contrast to allelic loss, the presence of both types of mutations (ITD and TKD) in a patient was not associated with a different clinical course. However, the precise prognostic relevance of FLT3-TKD mutations remains open. Although FLT3-TKD mutations had a similar effect on WBC counts and BM blasts and tended to be associated with lower OS and DFS, this association was not significant in most patients. In addition to the reasons discussed regarding the follow-up, we did not analyze the transforming activity of the different TKD mutations, which may differ considerably, as has been shown for the fms tyrosine kinase.44 Clearly, this must be done to elucidate the clinical importance of this change. Evidence for allelic loss at 13q12 with loss of the wt FLT3 allele (ie, mutant/wt ratio greater than 2) has recently also been reported by others.45 However, we did not find any evidence of genomic deletion in FISH assays using a 100-KBp BAC fragment corresponding to chromosomal region 13q12. To further clarify this issue, we performed differential PCR, which also failed to show significant differences in the allelic ratios between normal diploid samples and the patients. There are several potential explanations for this observation. First, the deletion could have involved only parts of the FLT3 gene, which stretches over a total of 35 kb. Alternatively the wt FLT3 gene could have been deleted by homologous recombination, a mechanism of loss of heterozygosity frequently observed in solid tumors.46 The substitution of the wt FLT3 allele by the mutant would explain why we did not observe a genomic deletion of this locus. The finding that FLT3 aberrations were abundant in patients with normal karyotype according to conventional cytogenetics and less frequent in patients with typical aberrations indeed points to a novel mechanism of leukemia development in this group of patients. Kiyoi et al20 postulated that the palindromic DNA sequence between codons 593 and 602 of FLT3 favors the formation of secondary structures, thus leading to the tandem mutation. Sequence analysis in 101 mutated FLT3 sequences in our study indicates that the main cluster of the mutations lies between codons 591 and 601, which supports this hypothesis. Nevertheless we observed a substantial number of patients without involvement of this stretch or the insertion of nucleotides not matching FLT3 sequences. This points to a more complex background of the FLT3 aberrations. Furthermore, 20 (16.5%) of the patients with FLT3-ITDs contained several clonally unrelated mutations, which indicates that FLT3 aberrations are potentially not the causative event but the result of an inherent genetic instability of the leukemic cells due to an as yet undefined defect. In this context, the association of FLT3 mutations with 2 translocations, t(15;17)/PML-RARA and t(6;9)/DEK-CAN, observed in our study deserves attention. FLT3-ITDs were observed in 90% of patients with DEK-CAN fusion (Table 2). The can gene on chromosome 9 codes for a part of the nucleoporin complex.47,48 In contrast, the role of the DEK protein is largely unknown. Meyn et al49 have shown that the carboxy-terminal 35 amino acids of DEK are able to revert the genetic instability of ataxia-telangiectasia-mutated (ATM) cells, indicating that DEK might function in controlling genetic stability. The DEK-CAN fusion protein lacks these terminal 35 amino acids. More recently, DEK has been shown to be important in the maintenance of chromatin structure and seems to be an essential part of the replication machinery.50 A significant increase of FLT3-ITD and TKD mutations was also observed in patients with t(15;17). The PML gene involved in t(15;17) is an interferon-inducible gene that encodes a RING-finger protein typically concentrated within nuclear structures called PML nuclear bodies or PML oncogenic domains.51 Overexpression of the PML protein induces growth arrest; however, the precise function of the protein is still not fully understood. Recently, the PML protein was found to interact with the Bloom syndrome gene, BLM, a RecQ DNA helicase whose absence induces genomic instability and high levels of sister-chromatid exchange, indicating that PML might also be involved in controlling genetic stability.52 Thus it is tempting to speculate that alterations of PML, DEK, or other proteins involved in chromosomal stability might be relevant in the development of FLT3-ITD. In summary our data indicate that FLT3 mutations are a common alteration in adult AML. Patients with the FLT3-ITD mutation and a loss of the wt-FLT3 allele seem to have a worse prognosis. In this regard, we believe that the use of fluorophore-labeled primer molecules and denaturing gel electrophoresis offers several advantages compared with conventional gel analysis. This mode of detection enables the unambiguous separation of single or multiple mutant FLT3 fragments. In addition, it allows calculation of a ratio between the mutant and the wt FLT3 alleles that might be more accurate and sensitive in the detection of allelic loss and that might add prognostic information to the qualitative detection of FLT3 alterations. This may help to identify high-risk patients who should potentially be offered more intensive treatment options. Clearly, the prognostic value of this ratio has to be analyzed in future prospective trials.
We thank all participating centers of the SHG AML-96 study ("Appendix"). S. Soucek and S. Freund provided excellent help in statistical analyses. The full-length cDNA clone of FLT3 was a kind gift of Dr O. Rosnet. We thank M. Hartwig, U. Löwel, M. Neumann, P. Grassmel, and C. Grosse for their skillful technical assistance. We thank Prof Joachim Deeg and Dr Michael Maris (Fred Hutchinson Cancer Research Center, Seattle, WA) for critically reading the manuscript.
Submitted July 17, 2001; accepted January 9, 2002.
Supported in part by grants from the Deutsche Krebshilfe (70-2210-Eh5) (G.E.). Supported by the Kompetenznetzwerk Akute und Chronische Leukämien, sponsored by the BMBF.
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 2334). Reprints: Christian Thiede, Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der Technischen Universität, Fetscherstrasse 74, 01307 Dresden, Germany; e-mail: thiede{at}mk1.med.tu-dresden.de.
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The following is a list of participating centers and physicians: D. Huhn, O. Knigge (Universitätsklinikum Charite, Berlin), R. Kolloch, U. Krümpelmann (Krankenanstalten Gilead, Bielefeld), K.-H. Pflüger, T. Wolff (Evang. Diakonissenanstalt Bremen), H.-H. Heidtmann (St Joseph-Hospital, Bremerhaven), F. Marquard (Allgemeines Krankenhaus, Celle), F. Fiedler, R. Herbst (Krankenhaus Küchwald, Chemnitz), M. Gramatzki, G. Helm (Universitätsklinikum, Erlangen), J.-G. Saal (Malteser Krankenhaus, Flensburg), H.-G. Höffkes, M. Arland (Städtisches Klinikum, Fulda), E. Faßhauer (St Elisabeth-Krankenhaus, Halle), R. Kuse (Allgemeines Krankenhaus St Georg, Hamburg), H. Schmidt, K. Buhrmann (Kreiskrankenhaus, Hameln), H. Dürk (St Marien-Hospital, Hamm), M. Burk (Klinikum Stadt, Hanau), A.-D. Ho, R. Weber-Nordt (Universitätsklinikum, Heidelberg), A. A. Fauser (Klinik f. Hämatologie/Onkologie und KMT, Idar-Oberstein), H. Link, F.-G. Hagmann (Westpfalzklinikum, Kaiserslautern), G. Köchling (Kreiskrankenhaus, Leer), K.-P. Schalk (St Vincent-Krankenhaus, Limburg/Lahn), S. Fetscher (Städtisches Krankenhaus Süd, Lübeck), T. Wagner (Universitätsklinikum, Lübeck), H. Bodenstein, J. Tischler (Klinikum Minden, Minden), H. Pohlmann, N. Brack (Städtisches Krankenhaus München-Harlaching, München), H. Wandt, K. Schäfer-Eckart, T. Denzel (Städtisches Klinikum, Nürnberg), B. Seeber (Klinikum Offenbach, Offenbach), F. Hirsch (Kreiskrankenhaus, Offenburg), T. Geer, H. Heißmeyer (Diakonie-Krankenhaus, Schwäbisch-Hall), J. Labenz (Ev. Jung-Stilling-Krankenhaus, Siegen), J. Kaesberger (Diakonissen-Krankenhaus, Stuttgart), W. E. Aulitzky, L. Leimer (Robert-Bosch-Krankenhaus, Stuttgart), M. R. Clemens, R. Mahlberg (Mutterhaus der Borromaerinnen, Trier), R. Schwerdtfeger (Deutsche Klinik für Diagnostik, Wiesbaden), R. Engberding, R. Winter (Stadtkrankenhaus, Wolfsburg), M. Sandmann (Klinikum St Antonius, Wuppertal), H. Rückle-Lanz, M. Wilhelm (Universitätsklinikum, Würzburg).
© 2002 by The American Society of Hematology.
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S. Vempati, C. Reindl, U. Wolf, R. Kern, K. Petropoulos, V. M. Naidu, C. Buske, W. Hiddemann, T. M. Kohl, and K. Spiekermann Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591 Clin. Cancer Res., July 15, 2008; 14(14): 4437 - 4445. [Abstract] [Full Text] [PDF]
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A. J. Mead, R. E. Gale, R. K. Hills, M. Gupta, B. D. Young, A. K. Burnett, and D. C. Linch Conflicting data on the prognostic significance of FLT3/TKD mutations in acute myeloid leukemia might be related to the incidence of biallelic disease Blood, July 15, 2008; 112(2): 444 - 445. [Full Text] [PDF]
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K. Dohner and H. Dohner Molecular characterization of acute myeloid leukemia Haematologica, July 1, 2008; 93(7): 976 - 982. [Full Text] [PDF]
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F. Lo-Coco, A. Cuneo, F. Pane, D. Cilloni, D. Diverio, M. Mancini, N. Testoni, A. Bardi, B. Izzo, N. Bolli, et al. Prognostic impact of genetic characterization in the GIMEMA LAM99P multicenter study for newly diagnosed acute myeloid leukemia Haematologica, July 1, 2008; 93(7): 1017 - 1024. [Abstract] [Full Text] [PDF]
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C. Langer, M. D. Radmacher, A. S. Ruppert, S. P. Whitman, P. Paschka, K. Mrozek, C. D. Baldus, T. Vukosavljevic, C.-G. Liu, M. E. Ross, et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study Blood, June 1, 2008; 111(11): 5371 - 5379. [Abstract] [Full Text] [PDF]
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S. Meshinchi, D. L. Stirewalt, T. A. Alonzo, T. J. Boggon, R. B. Gerbing, J. L. Rocnik, B. J. Lange, D. G. Gilliland, and J. P. Radich Structural and numerical variation of FLT3/ITD in pediatric AML Blood, May 15, 2008; 111(10): 4930 - 4933. [Abstract] [Full Text] [PDF]
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C. Nishioka, T. Ikezoe, J. Yang, A. Miwa, T. Tasaka, Y. Kuwayama, K. Togitani, H. P. Koeffler, and A. Yokoyama Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo Blood, May 15, 2008; 111(10): 5086 - 5092. [Abstract] [Full Text] [PDF]
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G. Marcucci, M. D. Radmacher, K. Maharry, K. Mrozek, A. S. Ruppert, P. Paschka, T. Vukosavljevic, S. P. Whitman, C. D. Baldus, C. Langer, et al. MicroRNA Expression in Cytogenetically Normal Acute Myeloid Leukemia N. Engl. J. Med., May 1, 2008; 358(18): 1919 - 1928. [Abstract] [Full Text] [PDF]
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M. H. Tomasson, Z. Xiang, R. Walgren, Y. Zhao, Y. Kasai, T. Miner, R. E. Ries, O. Lubman, D. H. Fremont, M. D. McLellan, et al. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia Blood, May 1, 2008; 111(9): 4797 - 4808. [Abstract] [Full Text] [PDF]
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L. Bullinger, K. Dohner, R. Kranz, C. Stirner, S. Frohling, C. Scholl, Y. H. Kim, R. F. Schlenk, R. Tibshirani, H. Dohner, et al. An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML Blood, May 1, 2008; 111(9): 4490 - 4495. [Abstract] [Full Text] [PDF]
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R. E. Gale, C. Green, C. Allen, A. J. Mead, A. K. Burnett, R. K. Hills, D. C. Linch, and on behalf of the Medical Research Council Adult Le The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia Blood, March 1, 2008; 111(5): 2776 - 2784. [Abstract] [Full Text] [PDF]
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U. Bacher, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients Blood, March 1, 2008; 111(5): 2527 - 2537. [Abstract] [Full Text] [PDF]
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H. Wandt, U. Schakel, F. Kroschinsky, G. Prange-Krex, B. Mohr, C. Thiede, U. Pascheberg, S. Soucek, M. Schaich, and G. Ehninger MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients Blood, February 15, 2008; 111(4): 1855 - 1861. [Abstract] [Full Text] [PDF]
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F. P. Kroschinsky, U. Schakel, R. Fischer, B. Mohr, U. Oelschlaegel, R. Repp, M. Schaich, S. Soucek, G. Baretton, G. Ehninger, et al. Cup-like acute myeloid leukemia: new disease or artificial phenomenon? Haematologica, February 1, 2008; 93(2): 283 - 286. [Abstract] [Full Text] [PDF]
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S. P. Whitman, A. S. Ruppert, M. D. Radmacher, K. Mrozek, P. Paschka, C. Langer, C. D. Baldus, J. Wen, F. Racke, B. L. Powell, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications Blood, February 1, 2008; 111(3): 1552 - 1559. [Abstract] [Full Text] [PDF]
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H.-G. Kim, K. Kojima, C. S. Swindle, C. V. Cotta, Y. Huo, V. Reddy, and C. A. Klug FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia Blood, February 1, 2008; 111(3): 1567 - 1574. [Abstract] [Full Text] [PDF]
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T. Haferlach Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia Hematology, January 1, 2008; 2008(1): 400 - 411. [Abstract] [Full Text] [PDF]
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M. M. Burnett, M. S. Huang, and R. M. Seliem Case 39-2007 -- A 5-Month-Old Girl with Skin Lesions N. Engl. J. Med., December 20, 2007; 357(25): 2616 - 2623. [Full Text] [PDF]
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E. V. Barry, J. J. Clark, J. Cools, J. Roesel, and D. G. Gilliland Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin Blood, December 15, 2007; 110(13): 4476 - 4479. [Abstract] [Full Text] [PDF]
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D. C. Link, G. Kunter, Y. Kasai, Y. Zhao, T. Miner, M. D. McLellan, R. E. Ries, D. Kapur, R. Nagarajan, D. C. Dale, et al. Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia Blood, September 1, 2007; 110(5): 1648 - 1655. [Abstract] [Full Text] [PDF]
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A. J. Mead, D. C. Linch, R. K. Hills, K. Wheatley, A. K. Burnett, and R. E. Gale FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia Blood, August 15, 2007; 110(4): 1262 - 1270. [Abstract] [Full Text] [PDF]
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G. Marcucci, K. Maharry, S. P. Whitman, T. Vukosavljevic, P. Paschka, C. Langer, K. Mrozek, C. D. Baldus, A. J. Carroll, B. L. Powell, et al. High Expression Levels of the ETS-Related Gene, ERG, Predict Adverse Outcome and Improve Molecular Risk-Based Classification of Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., August 1, 2007; 25(22): 3337 - 3343. [Abstract] [Full Text] [PDF]
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H. Kiyoi, Y. Shiotsu, K. Ozeki, S. Yamaji, H. Kosugi, H. Umehara, M. Shimizu, H. Arai, K. Ishii, S. Akinaga, et al. A Novel FLT3 Inhibitor FI-700 Selectively Suppresses the Growth of Leukemia Cells with FLT3 Mutations Clin. Cancer Res., August 1, 2007; 13(15): 4575 - 4582. [Abstract] [Full Text] [PDF]
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B. Sargin, C. Choudhary, N. Crosetto, M. H. H. Schmidt, R. Grundler, M. Rensinghoff, C. Thiessen, L. Tickenbrock, J. Schwable, C. Brandts, et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML Blood, August 1, 2007; 110(3): 1004 - 1012. [Abstract] [Full Text] [PDF]
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S. Vempati, C. Reindl, S. K. Kaza, R. Kern, T. Malamoussi, M. Dugas, G. Mellert, S. Schnittger, W. Hiddemann, and K. Spiekermann Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential Blood, July 15, 2007; 110(2): 686 - 694. [Abstract] [Full Text] [PDF]
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S. P. Whitman, A. S. Ruppert, G. Marcucci, K. Mrozek, P. Paschka, C. Langer, C. D. Baldus, J. Wen, T. Vukosavljevic, B. L. Powell, et al. Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study Blood, June 15, 2007; 109(12): 5164 - 5167. [Abstract] [Full Text] [PDF]
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U. Bacher, T. Haferlach, W. Kern, C. Haferlach, and S. Schnittger A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia Haematologica, June 1, 2007; 92(6): 744 - 752. [Abstract] [Full Text] [PDF]
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M. Schaich, R. F. Schlenk, H. K. Al-Ali, H. Dohner, A. Ganser, G. Heil, T. Illmer, R. Krahl, J. Krauter, C. Sauerland, et al. Prognosis of acute myeloid leukemia patients up to 60 years of age exhibiting trisomy 8 within a non-complex karyotype: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup Haematologica, June 1, 2007; 92(6): 763 - 770. [Abstract] [Full Text] [PDF]
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C. Graf, F. Heidel, S. Tenzer, M. P. Radsak, F. K. Solem, C. M. Britten, C. Huber, T. Fischer, and T. Wolfel A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells Blood, April 1, 2007; 109(7): 2985 - 2988. [Abstract] [Full Text] [PDF]
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D. Barbaric, T. A. Alonzo, R. B. Gerbing, S. Meshinchi, N. A. Heerema, D. R. Barnard, B. J. Lange, W. G. Woods, R. J. Arceci, and F. O. Smith Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961 Blood, March 15, 2007; 109(6): 2314 - 2321. [Abstract] [Full Text] [PDF]
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M. Bornhauser, T. Illmer, M. Schaich, S. Soucek, G. Ehninger, C. Thiede, and for the AML SHG 96 study group Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML Blood, March 1, 2007; 109(5): 2264 - 2265. [Full Text] [PDF]
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O. Piloto, M. Wright, P. Brown, K.-T. Kim, M. Levis, and D. Small Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways Blood, February 15, 2007; 109(4): 1643 - 1652. [Abstract] [Full Text] [PDF]
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S. Agrawal, M. Unterberg, S. Koschmieder, U. zur Stadt, U. Brunnberg, W. Verbeek, T. Buchner, W. E. Berdel, H. Serve, and C. Muller-Tidow DNA Methylation of Tumor Suppressor Genes in Clinical Remission Predicts the Relapse Risk in Acute Myeloid Leukemia Cancer Res., February 1, 2007; 67(3): 1370 - 1377. [Abstract] [Full Text] [PDF]
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B. Falini, I. Nicoletti, M. F. Martelli, and C. Mecucci Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features Blood, February 1, 2007; 109(3): 874 - 885. [Abstract] [Full Text] [PDF]
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K. Mrozek, G. Marcucci, P. Paschka, S. P. Whitman, and C. D. Bloomfield Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood, January 15, 2007; 109(2): 431 - 448. [Abstract] [Full Text] [PDF]
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T. Illmer, M. Schaich, G. Ehninger, C. Thiede, and on behalf of the DSIL2003 AML study group Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias Haematologica, January 1, 2007; 92(1): 137 - 138. [Abstract] [Full Text] [PDF]
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H. Dohner Implication of the Molecular Characterization of Acute Myeloid Leukemia Hematology, January 1, 2007; 2007(1): 412 - 419. [Abstract] [Full Text] [PDF]
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H. P. Erba Prognostic Factors in Elderly Patients with AML and the Implications for Treatment Hematology, January 1, 2007; 2007(1): 420 - 428. [Abstract] [Full Text] [PDF]
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C. Marzac, I. Teyssandier, O. Calendini, J.-Y. Perrot, A.-M. Faussat, R. Tang, N. Casadevall, J.-P. Marie, and O. Legrand Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia Clin. Cancer Res., December 1, 2006; 12(23): 7018 - 7024. [Abstract] [Full Text] [PDF]
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S. Meshinchi, T. A. Alonzo, D. L. Stirewalt, M. Zwaan, M. Zimmerman, D. Reinhardt, G. J. L. Kaspers, N. A. Heerema, R. Gerbing, B. J. Lange, et al. Clinical implications of FLT3 mutations in pediatric AML Blood, December 1, 2006; 108(12): 3654 - 3661. [Abstract] [Full Text] [PDF]
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M. Heuser, G. Beutel, J. Krauter, K. Dohner, N. von Neuhoff, B. Schlegelberger, and A. Ganser High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics Blood, December 1, 2006; 108(12): 3898 - 3905. [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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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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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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M. Camos, J. Esteve, P. Jares, D. Colomer, M. Rozman, N. Villamor, D. Costa, A. Carrio, J. Nomdedeu, E. Montserrat, et al. Gene Expression Profiling of Acute Myeloid Leukemia with Translocation t(8;16)(p11;p13) and MYST3-CREBBP Rearrangement Reveals a Distinctive Signature with a Specific Pattern of HOX Gene Expression. Cancer Res., July 15, 2006; 66(14): 6947 - 6954. [Abstract] [Full Text] [PDF]
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C. S. Wilson, G. S. Davidson, S. B. Martin, E. Andries, J. Potter, R. Harvey, K. Ar, Y. Xu, K. J. Kopecky, D. P. Ankerst, et al. Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction Blood, July 15, 2006; 108(2): 685 - 696. [Abstract] [Full Text] [PDF]
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C. D. Bloomfield, K. Mrozek, and M. A. Caligiuri Cancer and Leukemia Group B Leukemia Correlative Science Committee: Major Accomplishments and Future Directions. Clin. Cancer Res., June 1, 2006; 12(11): 3564s - 3571s. [Abstract] [Full Text] [PDF]
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U. Bacher, T. Haferlach, C. Schoch, W. Kern, and S. Schnittger Implications of NRAS mutations in AML: a study of 2502 patients Blood, May 15, 2006; 107(10): 3847 - 3853. [Abstract] [Full Text] [PDF]
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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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C. Reindl, K. Bagrintseva, S. Vempati, S. Schnittger, J. W. Ellwart, K. Wenig, K.-P. Hopfner, W. Hiddemann, and K. Spiekermann Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML Blood, May 1, 2006; 107(9): 3700 - 3707. [Abstract] [Full Text] [PDF]
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S. Schnittger, T. M. Kohl, T. Haferlach, W. Kern, W. Hiddemann, K. Spiekermann, and C. Schoch KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival Blood, March 1, 2006; 107(5): 1791 - 1799. [Abstract] [Full Text] [PDF]
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A. Shimada, T. Taki, K. Tabuchi, A. Tawa, K. Horibe, M. Tsuchida, R. Hanada, I. Tsukimoto, and Y. Hayashi KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group Blood, March 1, 2006; 107(5): 1806 - 1809. [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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F. Heidel, F. K. Solem, F. Breitenbuecher, D. B. Lipka, S. Kasper, M. H. Thiede, C. Brandts, H. Serve, J. Roesel, F. Giles, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain Blood, January 1, 2006; 107(1): 293 - 300. [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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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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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, 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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Top
Abstract
Introduction
autologous or allogeneic blood stem cell
transplantation
5/del(5q),
0.37; group 1) compared with patients
whose ratio was between the 26th and 74th
percentile (ratio > 0.37 
rearrangement. The rate of FLT3-ITDs in 10 patients with t(6;9), 9 of whom showed this mutation, was unexpectedly high. Given the low
frequency of the t(6;9) of approximately 1%,