Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human hematologic malignancies. An internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence of the FLT3 gene (FLT3-ITD) is found in 20-25% of adult acute myeloid leukemia (AML) and at a lower frequency in childhood AML. FLT3-ITD is associated with leukocytosis and a poor prognosis, especially in patients with normal karyotype. Recently, there have been three reports on point mutations at codon 835 of the FLT3 gene (D835 mutations) in adult AML. These mutations are located in the activation loop of the second tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD). The clinical and prognostic relevance of the TKD mutations is less clear. To the best of our knowledge, there has been no report to describe FLT3-TKD mutations in childhood AML. In this pediatric series, FLT3-TKD mutations occurred in three of 91 patients (3.3%), an incidence significantly lower than that of FLT3-ITD (14 of 91 patients, 15.4%) in the same cohort of patients. None of them had both FLT3-TKD and FLT3-ITD mutations. Sequence analysis showed one each of D835 Y, D835 V, and D835 H. Of the three patients carrying FLT3-TKD, two had AML-M3 with one each of L- and V-type PML-RARalpha, and another one had AML-M2 with AML1-ETO. None of our patients with FLT3-TKD had leukocytosis at diagnosis. At bone marrow relapse, one of the four patients examined acquired FLT3-ITD mutation and none gained FLT3-TKD mutation.
 ...
PMID:FLT3-TKD mutation in childhood acute myeloid leukemia. 1275 Jul 1

Partial tandem duplication (PTD) of the MLL gene and internal tandem duplication (ITD) of the juxtamembrane region of the FLT3 receptor tyrosine kinase gene have been described in acute myeloid leukemia (AML) patients, preferentially in those with normal cytogenetics. These alterations have been associated with a poor prognosis. In our study, we analyzed the prevalence and the potential prognostic impact of these aberrations in a large unselected and well-defined cohort of 956 patients with AML. Results were correlated with cytogenetic data and clinical outcome. MLL PTD was detected by RT-PCR, subsequent nucleotide sequencing, and Southern blotting. The overall incidence was found to be 5.0% (48/956), whereas FLT3 ITD was detected in 19.2% (184/956). Sixteen cases were positive for both alterations. The rate of MLL PTD in FLT3 ITD positive patients was significantly higher than that in FLT3 ITD negative patients [16/184 (8.7%); 32/772 (4.1%); P = 0.025]. However, both aberrations were highly increased in patients with normal karyotype (MLL PTD 35/431, P = 0.004; FLT3 ITD 132/334, P < 0.001). When restricted to this subgroup, the rate of MLL PTD in patients with FLT3 mutations was not significantly increased. No statistically significant differences were detected between patients positive for MLL PTD and patients negative for MLL PTD in the rate of complete remissions or the overall survival, although we did see a significantly shorter disease-free survival in patients age 60 or younger. In conclusion, although there is an overlap in the mutational spectrum in AML with FLT3 ITD and MLL PTD mutations, our data do not support a common mechanistic basis. Although associated with inferior disease-free survival, the results of this study do not unequivocally support the notion that MLL PTD mutations represent an independent prognostic factor.
 ...
PMID:Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. 1275 22

DNA from 110 adult de novo acute myeloid leukaemia (AML) patients exhibiting either inv(16) (n = 63) or t(8;21) (n = 47) was screened for mutations in the c-KIT (exon 8 and Asp816) and FLT3 (ITD and Asp835) genes. c-KIT exon 8 mutations were found in 15/63 (23.8%) inv(16) patients and 1/47 (2.1%) t(8;21) patients. c-KIT Asp816 mutations were present in 5/63 (7.9%) inv(16) AML and 5/47 (10.6%) t(8;21) AML. FLT3 mutations were identified in five patients (7.9%) with inv(16) and three patients (5.6%) with t(8;21) AML. All mutations were mutually exclusive; 40% of inv(16) AML patients possessed either a c-KIT or FLT3 mutation. c-KIT exon 8 mutations were shown to be a significant factor adversely affecting relapse rate.
 ...
PMID:Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. 1278 Jul 93

MLL rearrangements in acute myeloid leukemia (AML) include translocations and intragenic abnormalities such as internal duplication and breakage induced by topoisomerase II inhibitors. In adult AML, FLT3 internal tandem duplications (ITDs) are more common in cases with MLL intragenic abnormalities (33%) than those with MLL translocation (8%). Mutation/deletion involving FLT3 D835 are found in more than 20% of cases with MLL intragenic abnormalities compared with 10% of AML with MLL translocation and 5% of adult AML with normal MLL status. Real-time quantification of FLT3 in 141 cases of AML showed that all cases with FLT3 D835 express high level transcripts, whereas FLT3-ITD AML can be divided into cases with high-level FLT3 expression, which belong essentially to the monocytic lineage, and those with relatively low-level expression, which predominantly demonstrate PML-RARA and DEK-CAN. FLT3 abnormalities in CBF leukemias with AML1-ETO or CBFbeta-MYH11 were virtually restricted to cases with variant CBFbeta-MYH11 fusion transcripts and/or atypical morphology. These data suggest that the FLT3 and MLL loci demonstrate similar susceptibility to agents that modify chromatin configuration, including topoisomerase II inhibitors and abnormalities involving PML and DEK, with consequent errors in DNA repair. Variant CBFbeta-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms.
 ...
PMID:FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. 1279 58

STAT5 phosphorylation has been noted in 69-95% of AML cases by Western blotting. We used flow cytometry to measure phosphorylated STAT5 on a semi-quantitative scale. The method was validated on K562 cells, which constitutively express phosphorylated STAT5, but lose this when BCR-abl tyrosine kinase activity is blocked by STI571. Phosphorylated STAT5 was found to measure 2.22+/-0.09 relative fluorescence units (RFU) falling to 0.925+/-0.005RFU in the presence of STI571. Phosphorylated STAT5 expression was 0.99 to 2.09RFU in 28 primary AML samples. There was no logical cut-off point between positive and negative fluorescence. FLT3 internal tandem duplications, found in 11/28 samples, were not significantly associated with the level of phosphorylated STAT5 expression. We conclude that STAT5 phosphorylation can be measured sensitively by flow cytometry in AML and that its expression should not be dichotomised as present or absent.
 ...
PMID:Flow cytometric measurement of phosphorylated STAT5 in AML: lack of specific association with FLT3 internal tandem duplications. 1280 38

The receptor tyrosine kinase FLT3 is constitutively activated by an internal tandem duplication (ITD) mutation within the juxtamembrane domain in 20-30% of patients with acute myeloid leukemia. In this study, we identified GTP-14564 as a specific kinase inhibitor for ITD-FLT3 and investigated the molecular basis of its specificity. GTP-14564 inhibited the growth of interleukin-3-independent Ba/F3 expressing ITD-FLT3 at 1 microM, whereas a 30-fold higher concentration of GTP-14564 was required to inhibit FLT3 ligand-dependent growth of Ba/F3 expressing wild type FLT3 (wt-FLT3). However, this inhibitor suppressed the kinase activities of wt-FLT3 and ITD-FLT3 equally, suggesting that the signaling pathways for proliferation differ between wt-FLT3 and ITD-FLT3. Analysis of downstream targets of FLT3 using GTP-14564 revealed STAT5 activation to be essential for growth signaling of ITD-FLT3. In contrast, wt-FLT3 appeared to mainly use the MAPK pathway rather than the STAT5 pathway to transmit a proliferative signal. Further analysis demonstrated that the first two tyrosines in an ITD were critical for STAT5 activation and growth induction but that all of the tyrosines in the juxtamembrane region were dispensable in terms of the proliferation signals of wt-FLT3. These results indicate that an ITD mutation in FLT3 elicits an aberrant STAT5 activation that results in increased sensitivity to GTP-14564. Thus, FLT3-targeted inhibition is an attractive approach, with the potential for selective cytotoxicity, to the treatment of ITD-FLT3-positive acute myeloid leukemia.
 ...
PMID:Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). 1281 52

FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. FLT3 internal tandem duplications (FLT3/ITDs) are reported in acute myeloid leukemia (AML) and predict poor clinical outcome. We found FLT3/ITDs in 11.5% of 234 children with de novo AML. FLT3/ITD-positive patients were significantly older and had higher percentages of normal cytogenetic findings or French-American-British (FAB) classification M1/M2 and lower percentages of 11q23 abnormalities or FAB M5. FLT3/ITD-positive patients had lower remission induction rates (70% vs 88%; P =.01) and lower 5-year probability rates of event-free survival (pEF) (29% vs 46%; P =.0046) and overall survival (32% vs 58%; P =.037). Patients with high ratios (higher than the median) between mutant and wild-type FLT3 had significantly worse 2-year EFS rates than FLT3/ITD-negative patients (pEFS 20% vs 61%; P =.037), whereas patients with ratios lower than the median did not (pEFS 44% vs 61%; P =.26). FLT3/ITD was the strongest independent predictor for pEFS, with an increase in relative risk for an event of 1.92 (P =.01). Using an MTT (methyl-thiazol-tetrazolium)-based assay, we studied cellular drug resistance on 15 FLT3/ITD-positive and 125 FLT3/ITD-negative AML samples, but we found no differences in cellular drug resistance that could explain the poor outcomes in FLT3/ITD-positive patients. We conclude that FLT3/ITD is less common in pediatric than in adult AML. FLT3/ITD is a strong and independent adverse prognostic factor, and high ratios between mutant and WT-FLT3 further compromise prognosis. However, poor outcomes in FLT3/ITD-positive patients could not be attributed to increased in vitro cellular drug resistance.
 ...
PMID:FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. 1281 73

An internal tandem duplication (ITD) of the juxtamembrane (JM) domain of FLT3 (FLT3/ITD) has been found in 20% of patients with acute myeloid leukemia (AML) and is correlated with leukocytosis and a poor prognosis. Here, we compared the antiapoptotic effects of wild-type FLT3 (WtFLT3) and FLT3/ITD in terms of the regulation of Bcl-2 family members. In a murine myeloid cell line, 32D, interleukin-3 (IL-3) deprivation induced apoptosis following the down-regulation of Bcl-XL and the dephosphorylation of Bad. However, the expression levels of Bcl-2, Bax, Bak, and Mcl-1 were unchanged. In WtFLT3-transfected 32D (WtFLT3-32D) cells, FLT3 ligand (FL) stimulation did not restore the down-regulation of Bcl-XL but maintained the phosphorylation of Bad. Combined treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, dephosphorylated Bad and induced apoptosis in WtFLT3-32D cells stimulated with FL. Induction of nonphosphorylated Bad induced remarkable apoptosis. These findings suggest that the FL stimulation is associated with antiapoptosis through Bad phosphorylation. On the other hand, FLT3/ITD-transfected 32D (FLT3/ITD-32D) cells survived in an IL-3-or FL-deprived state. Furthermore, the dephosphorylation of Bad using LY294002 and PD98059 was insufficient for apoptosis, and the down-regulation of Bcl-XL using antisense treatment was needed to induce apoptosis. FLT3 kinase inhibitor, AG1296, alone not only dephosphorylated Bad but also down-regulated Bcl-XL, leading FLT3/ITD-32D cells into apoptosis. These findings suggest that the antiapoptotic pathways from FLT3/ITD are more divergent than those from WtFLT3 and may represent targets for drug discovery with the potential of inducing selective cell death of human leukemia cells.
 ...
PMID:Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia. 1284 96

Several studies have shown that mutations in the FLT3 gene are common events in AML, with approximately one third of adult patients harbouring either an internal tandem duplication in the juxtramembrane domain or a D835 mutation in the kinase domain. The majority of studies in pediatric and adult AML have shown that FLT3 mutations are powerful prognostic factors predicting for increased relapse risk and adverse overall survival. Some reports have suggested that loss of the wild type allele might be associated with an even worse prognosis. Changes in the pattern of FLT3 mutations between disease presentation and relapse restrict their value as a marker of minimal residual disease, and have significant implications for therapy. The optimum treatment for patients with FLT3 mutations remains unknown and large prospective studies are warranted to evaluate the efficacy of various treatment modalities such as bone marrow transplantation and targeted therapy with tyrosine kinase inhibitors.
 ...
PMID:Prognostic implications of the presence of FLT3 mutations in patients with acute myeloid leukemia. 1285 87

Tyrosine kinases are commonly mutated and activated in both acute and chronic myeloid leukemias. Here, we review the functions, signaling activities, mechanism of transformation, and therapeutic targeting of two prototypic tyrosine kinase oncogenes, BCR-ABL and FLT3, associated with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), respectively. BCR-ABL is generated by the Philadelphia chromosome translocation between chromosomes 9 and 22, creating a chimeric oncogene in which the BCR and c-ABL genes are fused. The product of this oncogene, BCR-ABL, has elevated ABL tyrosine kinase activity and transforms hematopoietic cells by exerting a wide variety of biological effects, including reduction in growth factor dependence, enhanced viability, and altered adhesion of chronic myelocytic leukemia (CML) cells. Elevated tyrosine kinase activity of BCR-ABL is critical for activating downstream signalling cascades and for all aspects of transformation, explaining the remarkable clinical efficacy of the tyrosine kinase inhibitor, imatinib mesylate (STI571). By comparison, FLT3 is mutated in about one third of all cases of AML, most often through a mechanism that involves an internal tandem duplication (ITD) of a small number of amino acid residues in the juxtamembrane domain of the receptor. As is the case for BCR-ABL, these mutations activate the kinase activity constitutively, activate multiple signaling pathways, and result in an augmentation of proliferation and viability. Transformation by FLT3-ITD can readily be observed in murine models, and FLT3 cooperates with other types of oncogenes to create a fully transformed acute leukemia. FLT3 tyrosine kinase inhibitors are currently being evaluated in clinical trials and may be very useful therapeutic agents in AML.
 ...
PMID:Mutated tyrosine kinases as therapeutic targets in myeloid leukemias. 1290 54


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>