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)

Acute lymphoblastic leukemia (ALL) in infants is characterized by rearrangements of the mixed lineage leukemia (MLL) gene, drug resistance, and a poor treatment outcome. Therefore, novel therapeutic strategies are needed to improve prognosis. Recently, we showed that FLT3 is highly expressed in MLL rearranged ALL (MLL). Here we demonstrate FLT3 expression in infants with MLL (n = 41) to be significantly higher compared to both infant (n = 8; P < .001) and noninfant patients with ALL (n = 23; P = .001) carrying germline MLL genes. Furthermore, leukemic cells from infants with MLL were significantly more sensitive to the Fms-like tyrosine kinase 3 (FLT3) inhibitor PKC412 (N-benzoyl staurosporine) than noninfant ALL cells, and at least as sensitive as internal tandem duplication-positive (ITD+) AML cells. Surprisingly, activation loop mutations only occurred in about 3% (1 of 36) of the cases and no FLT3/ITDs were observed. However, measuring FLT3 phosphorylation in infants with MLL expressing varying levels of wild-type FLT3 revealed that high-level FLT3 expression is associated with ligand-independent FLT3 activation. This suggests that infant MLL cells displaying activated FLT3 as a result of overexpression can be targeted by FLT3 inhibitors such as PKC412. However, at concentrations of PKC412 minimally required to fully inhibit FLT3 phosphorylation, the cytotoxic effects were only fractional. Thus, PKC412-induced apoptosis in infant MLL cells is unlikely to be a consequence of FLT3 inhibition alone but may involve inhibition of multiple other kinases by this drug.
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PMID:Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia. 1595 79

Genomic aberrations of Fms-like tyrosine kinase 3 (FLT3), including internal tandem duplication (ITD) and point mutations, have been demonstrated in 25-30% of adults acute myeloid leukemia (AML) and are markers of poor prognosis. FLT3/ITD and D835 mutations were analyzed in 194 Chinese patients with acute leukemia and myelodysplastic syndromes (MDS) by polymerase chain reaction (PCR). FLT3/ITDs and D835 mutations were found in 25.9 and 6.3% of 143 AML patients, respectively. Two patients showed both ITD and point mutations. Among the FAB subtypes of AML, the rate of FLT3 aberration was significantly higher in M3 and M5. However, neither aberrations was found in 25 patients with acute lymphoblastic leukemia (ALL), 2 acute hybrid leukemia, 17 MDS and 7 chronic myeloid leukemia in blast crisis (CML-BC). FLT3/ITD was associated to leukocytosis and lower complete remission (CR) rate, and was more prevalent in patients with normal karyotype. In contrast, D835 mutation was not associated with leukocytosis or low CR rate. Our results confirm that FLT3 activating mutations also occur in a significant percentage in Chinese AML patients. FLT3/ITD(+) patients treated with standard induction regimen could achieve lower complete remission rates compared with patients not harboring this defect. Early detection of FLT3 mutations and an intensification of induction therapy might thus be useful for this group of patients to overcome the poor prognosis.
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PMID:Analysis of FLT3 internal tandem duplication and D835 mutations in Chinese acute leukemia patients. 1599 32

Fms-like tyrosine kinase 3 (Flt3) is a type III receptor tyrosine kinase. The internal tandem duplication (ITD) of the juxtamembrane region of this receptor is the most prevalent mutation in acute myeloid leukaemia (AML). The silencing mediator of retinoic and thyroid hormone receptors (SMRT) co-repressor recruits histone deacetylases (HDAC) and mediates transcriptional repression by interacting with various transcription factors. We recently reported that Flt3-ITD interferes with the transcriptional and biological action of promyelocytic leukaemia zinc finger transcriptional repressor by dissociating it from SMRT. In this study, we aimed to clarify whether the repressional activity of other well-known oncoproteins, such as AML1/Runx1 (AML1), is also affected by Flt3-ITD. We verified that the repression activity of AML1B, the isoform of AML1, is dependent on HDAC activity by using HDAC inbitor trichostatin A in GAL4 reporter assays. Mammalian two-hybrid assays demonstrated that this protein interacts with SMRT. Furthermore, this AML1B-SMRT interaction was disrupted by the overexpression of Flt3-ITD, leading to the reduction of AML1B repression activity. Additionally, we showed AML1B repression target, p21 (WAF1/CIP1), was aberrantly expressed in Flt3-ITD stably expressed BaF3 cells. Taken together, Flt3-ITD disrupts transcriptional repressor functions resulting in aberrant gene regulation in leukaemic cells.
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PMID:AML1B transcriptional repressor function is impaired by the Flt3-internal tandem duplication. 1604 94

Nucleophosmin (NPM1) exon-12 gene mutations are the hallmark of a large acute myelogenous leukemia (AML) subgroup with normal karyotype, but their prognostic value in this AML subset has not yet been determined. We screened 401 AML patients with normal karyotype treated within the German AML Cooperative Group Protocol 99 (AMLCG99) study for NPM1 mutations. Results were related with partial tandem duplications within the MLL gene (MLL-PTD), Fms-like tyrosine kinase 3-length mutations (FLT3-LM), the tyrosine kinase domain of FLT3 (FLT3-TKD), NRAS, KIT, and CEBPA mutations and with clinical characteristics and outcome. NPM1 mutations were detected in 212 (52.9%) of 401 patients. Fourteen mutations, including 8 new variants, were identified. NPM1-mutated cases associated frequently with FLT3 mutations but rarely with other mutations. The NPM1-mutated group had a higher complete remission (CR) rate (70.5% vs 54.7%, P = .003), a trend to a longer overall survival (OS; median 1012 vs 549 days, P = .076), and significantly longer event-free survival (EFS; median 428 vs 336 days; P = .012). The favorable impact of NPM1 mutations on OS and EFS clearly emerged in the large group (264 [66.8%] of 395 cases) of normal-karyotype AML without FLT3-LM. This positive effect was lost in the presence of a concomitant FLT3-LM, since survival of the NPM1+/FLT3-LM+ double positive was similar to NPM1-/FLT3-LM+ cases. In conclusion, this study demonstrates that NPM1+/FLT3-LM- mutations are an independent predictor for a favorable outcome in AML with normal karyotype.
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PMID:Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. 1607 67

Fetal liver tyrosine kinase 3 (FLT3) internal tandem duplications (ITDs) are powerful adverse prognostic indicators for relapse in acute myeloid leukemia (AML) but the most efficacious therapy for FLT3/ITD(+) patients is currently unknown. We evaluated outcome according to FLT3/ITD status in 1135 adult patients treated according to United Kingdom Medical Research Council (UK MRC) AML protocols: 141 received an autograft, and 170 received a matched sibling allograft in first complete remission (CR). An FLT3/ITD was detected in 25% of patients and was an independent predictor for relapse (P < .001). It remained prognostic for increased relapse in patients who received a transplant (odds ratio [OR] = 1.91; 95% confidence intervals [CIs] = 1.13-3.21; P = .02), with no evidence of a difference in effect between patients who received an autograft (OR = 2.39; CIs = 1.24-4.62) and patients who received an allograft (OR = 1.31; CIs = 0.56-3.06) (test for interaction, P = .3) or between patients who did or did not receive a transplant (P = .4). These results were confirmed in an analysis of 186 patients randomized to receive or not receive an autograft in first CR and in a donor-versus-no donor analysis of 683 patients to assess the role of allograft (for latter, FLT3/ITD(-) OR = 0.70, CIs = 0.53-0.92; FLT3/ITD(+) OR = 0.59, CIs = 0.40-0.87; test for interaction, P = .5). These results suggest that at present there is no strong evidence that FLT3 status should influence the decision to proceed to transplantation.
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PMID:No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. 1731 1

Activating FMS-like tyrosine kinase 3 (FLT3) mutations have been identified in approximately 30% of patients with acute myelogenous leukemia (AML), and recently in a smaller subset of patients with acute lymphoblastic leukemia (ALL). To explore the in vivo consequences of an activating FLT3 internal tandem duplication mutation (FLT3-ITD), we created a transgenic mouse model in which FLT3-ITD was expressed under the control of the vav hematopoietic promoter. Five independent lines of vav-FLT3-ITD transgenic mice developed a myeloproliferative disease with high penetrance and a disease latency of 6-12 months. The phenotype was characterized by splenomegaly, megakaryocytic hyperplasia, and marked thrombocythemia, but without leukocytosis, polycythemia, or marrow fibrosis, displaying features reminiscent of the human disease essential thrombocythemia (ET). Clonal immature B- or T-lymphoid disease was observed in two additional founder mice, respectively, that could be secondarily transplanted to recipient mice that rapidly developed lymphoid disease. Treatment of these mice with the FLT3 tyrosine kinase inhibitor, PKC412, resulted in suppression of disease and a statistically significant prolongation of survival. These results demonstrate that FLT3-ITD is capable of inducing myeloproliferative as well as lymphoid disease, and indicate that small-molecule tyrosine kinase inhibitors may be an effective treatment for lymphoid malignancies in humans that are associated with activating mutations in FLT3.
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PMID:FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. 1611 83

Activating mutations of Fms-like tyrosine kinase 3 (Flt3) are the most common genetic lesions in acute myeloid leukemia (AML) and are present in approximately one third of AML patients. The 2 classes of Flt3 mutations are internal tandem duplications in the juxtamembrane domain and point mutations in the tyrosine kinase domain. In normal hematopoietic progenitor cells, Flt3 ligand induces the activation of several downstream signal-transduction mediators, including phosphoinositol 3-kinases, Src kinases, mitogen-activated protein kinases, and the phosphorylation of several adaptor proteins. Oncogenic mutations in Flt3 result in ligand-independent constitutive and deregulated activation of these signaling pathways. In addition, however, oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. Aberrant activation of these signaling pathways by oncogenic Flt3 may play a critical role in mutant Flt3-mediated leukemic transformation.
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PMID:Signal transduction of oncogenic Flt3. 1614 38

Leukemias are differentially sensitive to histone deacytelase inhibitor (HDI)-induced apoptosis, but molecular reasons for this remain unclear. We here show that BCR/ABL-, but not FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-transformed 32D cells or primary acute myeloid leukemia (AML) blasts undergo apoptosis after treatment with the HDI valproic acid (VPA) plus all-trans retinoic acid (VPA/ATRA). A particular VPA/ATRA responsiveness of Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) was confirmed in a therapy-refractory patient in vivo. HDI-stimulated apoptosis in Ph+ cells was caspase dependent, but independent from Akt pathway inhibition. Conversely, separate blockage of the Akt/mTor-signaling pathway was a prerequisite for overcoming apoptosis resistance to VPA/ATRA in FLT3-ITD cells, and primary AML blasts (n = 9). In conclusion, constitutive Akt activation causes apoptosis resistance to VPA/ATRA in AML, but not in Ph+ leukemia. This warrants the application of HDI-based therapies in poor-risk Ph+ ALL, and the use of Akt/mTor inhibitors to overcome HDI resistance in AML.
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PMID:FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment. 1630 46

Although there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up to 40% of AML patients. Additionally, relapses are common in 50-70% of patients who achieve a complete remission, and only 20-30% of patients enjoy long-term disease-free survival. The natural history of myelodysplastic syndrome (MDS) is variable, with about half of the patients dying from cytopenic complications, and an additional 20-30% transforming to AML. The advanced age of the majority of MDS patients limits the therapeutic strategies often to supportive care. To address these shortcomings, much effort has been directed toward the development of novel treatment strategies that target the evolution and proliferation of malignant clones. Presented here is an overview of molecularly targeted therapies currently being tested in AML and MDS patients, with a focus on FMS-like tyrosine kinase 3 inhibitors, farnesyltransferase inhibitors, antiangiogenesis agents, DNA hypomethylation agents, and histone deacetylase inhibitors.
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PMID:Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias. 1639 11

Ligand-mediated activation of the FMS-like tyrosine kinase 3 (FLT3) receptor is important for normal proliferation of primitive hematopoietic cells. However, activating mutations in FLT3 induce ligand-independent downstream signaling that promotes oncogenesis through pathways involved in proliferation, differentiation, and survival. FLT3 mutations are identified as the most frequent genetic abnormality in acute myeloid leukemia and are also observed in other leukemias. Multiple small-molecule inhibitors are under development to target aberrant FLT3 activity that confers a poor prognosis in patients.
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PMID:FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia. 1641 Mar 83


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