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

FLT3 is a receptor tyrosine kinase that may play a role in a significant proportion of leukemias. In addition to being aberrantly expressed in acute leukemias, activating mutations of the FLT3 gene have been found in patients with AML, myelodysplastic syndrome (MDS) and more rarely, ALL. Internal tandem duplications (ITDs) of the FLT3 gene have been detected in 17-34% of patients with AML and portend a poor prognosis for these patients. FLT3 receptors containing ITD mutations (FLT3/ITDs) are constitutively activated in the absence of FLT3 ligand (FL) stimulation leading to the activation of downstream signaling proteins, including ERK and STAT 5. FLT3 activity, therefore, is a logical target for therapeutic intervention. AG1296 is a tyrosine kinase inhibitor of the tyrphostin class that shows inhibitory activity for wild-type FLT3, in addition to the PDGF and c-KIT receptors. We examined the inhibitory effects of AG1296 on FLT3/ITDs isolated from AML patients in the IL-3-dependent cell line, Ba/F3, as well as in primary leukemia samples from AML patients. Immunoprecipitation and immunoblotting analyses demonstrated that FLT3/ITDs were constitutively phosphorylated in the absence of FL. The auto-phosphorylation of FLT3/ITDs was inhibited by AG1296 with an IC(50) of approximately 1 microM. FLT3/ITDs were associated with constitutive phosphorylation of ERK, STAT 5A, STAT 5B, CBL, VAV and SHP2 in Ba/F3 cells. The phosphorylation of these downstream signaling molecules was suppressed in a dose-responsive fashion by AG1296. AG1296 inhibited IL-3 independent growth and induced apoptosis in Ba/F3 cells transformed by FLT3/ITDs. AG1296 also inhibited FLT3 auto-phosphorylation, and induced a cytotoxic effect, in primary AML cells. These findings suggest that inhibiting the activity of FLT3 may have a therapeutic value in some leukemias expressing FLT3/ITDs.
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PMID:Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. 1235 54

Activating length mutations in the juxtamembrane (JM) domain of the FLT3 gene (FLT3-LM) and mutations in the catalytic domain (FLT3D835/836) of this receptor tyrosine kinase represent the most frequent genetic alterations in acute myeloid leukemia (AML). Here, we describe a 6-bp insertion in the activation loop of FLT3 between codons 840 and 841 of FLT3 (FLT3-840GS) in 2 unrelated patients with AML. Screening for other activating mutations of FLT3, KIT, and NRAS showed no further genetic alterations in patients carrying the FLT3-840GS. In functional analyses we could show that this mutant is hyperphosphorylated on tyrosine and confers interleukin 3-independent growth to Ba/F3 cells, which can be inhibited by a specific FLT3 protein tyrosine kinase (PTK) inhibitor. Our results show for the first time that in addition to known mutations in the JM and the catalytic domain, further activating length mutations exist in the FLT3 gene.
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PMID:A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. 1238 47

Significant advances have occurred in understanding the molecular pathogenesis of human leukemias. Analysis of patient karyotypes reveals that nonrandom, somatically acquired translocations and inversions occur in most acute myeloid leukemias. Among these, fusion oncogenes have been identified that utilize similar signal transduction pathways and transcriptional activation pathways to mediate their leukemogeneic effect. In chronic myeloid leukemia (CML), both in vitro and in vivo animal studies show that BCR-AB expression leads to clinical manifestations of CML, demonstrating that BCR-AB and its fusion proteins are central mediators of myeloid proliferation and transformation in these malignancies. In other CML syndromes (chronic myelomonocytic leukemia, atypical CML), cloning of chromosomal translocation breakpoints has identified a spectrum of constitutively activated tyrosine kinases. These tyrosine kinase fusions alone apparently are both necessary and sufficient to recapitulate the disease phenotype in the murine model. In contrast, acute myelogenous leukemia (AML) is typified by chromosomal translocations involving transcription factors needed for normal myeloid differentiation. The functional consequence of translocations is loss of function of these transcription factors, resulting in impaired myeloid differentiation. However, these alone are not sufficient to cause acute leukemia; evidence strongly supports the hypothesis that second mutations are required. Data suggest a multistep pathogenesis for AML in which class I mutations, such as activating point mutations in receptor tyrosine kinases (eg, FLT3 and c-KIT), provide a proliferative and/or survival signal to hematopoietic progenitors. Class II mutations are those targeting hematopoietic transcription factors and serving primarily to impair differentiation and subsequent apoptosis. Together, these mutations result in leukemic cells capable of proliferation and survival but not differentiation. The clinical and therapeutic implication is that it may be possible to target both classes of mutations using selected or screened small-molecule inhibitors. Insights gained from molecular genetic analysis of AML provide the basis for a rational, targeted therapeutic approach.
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PMID:Molecular genetics of human leukemias: new insights into therapy. 1244 46

Childhood acute myeloid leukemia is a heterogeneous group of disorders that remains challenging to treat. There are multiple common genetic alterations in childhood acute myeloid leukemia. These include chromosomal translocations affecting RUNX1-CBFbeta, RARalpha, and MLL. There are known activating mutations in the genes for the receptor tyrosine kinases FLT3, KIT, and FMS. As these abnormalities are better understood, they are providing important insights into the pathogenesis of disease as well as information about prognosis. Although intensive chemotherapy remains the mainstay of acute myeloid leukemia therapy, long-term cure rates with chemotherapy alone remain approximately 50%, creating an urgent need for better therapies. Multiple avenues are being explored in the design of new treatments for pediatric acute myeloid leukemia. Targeted therapies include targeted antibody therapy; inhibitors of FLT3, KIT, and farnesyltransferase; diphtheria toxin conjugated to the granulocyte-macrophage colony-stimulating factor; and antisense oligonucleotides. Another area of interest is chromatin remodeling and differentiation therapy, including agents such as all- retinoic acid, arsenic trioxide, and inhibitors of DNA methylation and histone deacetylation. There are also ongoing trials of antiangiogenesis agents. Another avenue for novel therapies is immunotherapy with agents such as interleukin-2 and tumor vaccines. This article reviews recent advances in understanding of the molecular basis for childhood acute myeloid leukemia and the design of novel therapies for the treatment of childhood acute myeloid leukemia.
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PMID:Update in childhood acute myeloid leukemia: recent developments in the molecular basis of disease and novel therapies. 1248 9

FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.
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PMID:SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. 1253 5

Trisomy 8 is the most common chromosomal aberration in myelocytic malignancies, occurring both as a sole change as well as in addition to other abnormalities. In spite of this, next to nothing is known about its pathogenetic importance or its molecular genetic consequences. Possible mechanisms involved in the transformation process include dosage effects of genes mapping to chromosome 8 and presence of specific mutations or cryptic fusion genes on the duplicated chromosome. In the latter case, +8 would be secondary to a cryptic primary rearrangement and not involved in leukemogenesis as such, but rather in tumor evolution. Although hidden genetic changes have been found in some trisomies, for example, mutations in KIT in acute myelocytic leukemia (AML) with +4 and in MET in hereditary papillary kidney carcinoma with trisomy 7, none associated with +8 have so far been discovered. To address this issue, we have investigated a total of 13 cases of AML, myelodysplastic syndromes, and chronic myeloproliferative disorders with trisomy 8 as the sole chromosomal anomaly. All cases were studied by combined binary ratio multicolor fluorescence in situ hybridization (FISH) and with FISH using locus-specific probes for both arms of chromosome 8, the subtelomeric regions of 8p and 8q, and the leukemia-associated genes FGFR1, MOZ, ETO, and MYC. No cryptic changes were detected, thus excluding the possibility of gross genetic rearrangements or aberrations involving these loci on chromosome 8.
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PMID:Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies: a multicolor and locus-specific fluorescence in situ hybridization study. 1449 2

Despite maturation arrest, blast cells in acute myeloid leukemia (AML) are often capable of expressing lineage-restricted (granulomonocytic or myelomastocytic) differentiation antigens. Tryptases are lineage-associated serine proteases primarily expressed in mast cells, and less abundantly in blood basophils. We have recently shown that myeloblasts in a group of patients with AML (approximately 40%) produce significant amounts of tryptase(s). In these patients, serum tryptase levels are elevated (> 15 ng/ml) and reflect the total burden of leukemic cells. In most cases, myeloblasts express alpha-tryptase mRNA in excess over beta-tryptase mRNA, and secrete the respective protein (= pro-alpha-tryptase) in a constitutive manner. It was also found that these AML blasts frequentlyco-express tryptase with additional mast cell lineage- and/or basophil-related differentiation antigens including KIT (CD117), histamine, and 2D7. We hypothesize that tryptase-positive AMLs arise from a leukemic progenitor that exhibits a limited potential to differentiate into mast cells and/or basophils.
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PMID:Tryptase a novel biochemical marker of acute myeloid leukemia. 1261 10

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.
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PMID:Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. 1278 Jul 93

Mutations in the proto-oncogene c-kit cause constitutive kinase activity of its product, KIT protein, and are associated with human mastocytosis and gastrointestinal stromal tumors (GISTs). Although currently available tyrosine kinase inhibitors are effective in the treatment of GISTs, there has been limited success in the treatment of mastocytosis. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinoid ansamycin antibiotic, which binds to heat shock protein 90 (hsp90) causes destabilization of various hsp90-dependent kinases important in oncogenesis. Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure. These data were validated using Cos-7 cells transfected with wild-type and mutated KIT. 17-AAG promotes cell death of both HMC mast cell lines. In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction. These data provide compelling evidence that 17-AAG may be effective in the treatment of c-kit-related diseases including mastocytosis, GISTs, mast cell leukemia, subtypes of acute myelogenous leukemia, and testicular cancer.
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PMID:17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. 1455 Nov 38

KIT and FMS, members of the class III receptor tyrosine kinase family, are expressed on normal hematopoietic cells and have important roles in normal hematopoiesis. FLT3 is also a member of the class III receptor tyrosine kinase family and plays important role in hematopoietic stem/progenitor cells, NK, and dendritic cells. Recently, internal tandem duplication (ITDs) mutations have been found in the juxtamembrane (JM) region of FLT3 receptor expressed by patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The mutations result in the constitutive dimerization and activation of the receptor, contributing to leukemic transformation. KIT and FMS are also frequently expressed in AML and are closely related to FLT3. Thus, similar ITD mutations could also occur in the KIT and/or FMS gene of patients with AML. To explore this possibility, 13 human leukemia-lymphoma cell lines and 44 AML patient samples were examined by reverse transcription-polymerase chain reaction (RT-PCR) for the presence of ITD mutations in the JM region of the KIT or FMS receptor. None of the 13 human leukemia-lymphoma cell lines or 44 AML primary bone marrow samples express ITDs in either KIT or FMS in the JM region that is involved in FLT3 mutations. The 13 cell lines and 44 AML samples were also examined for the possible co-expression of KIT and/or FMS receptors with their respective ligands, as we have seen for FLT3 and its ligand, FL. This co-expression could contribute to leukemic transformation through autocrine, paracrine, or intracrine activation mechanisms. And 6/13 cell lines and 27/44 primary AML samples exhibit co-expression of the KIT receptor and ligand (SCF) while 10/13 cell lines and 35/44 primary AML samples exhibit co-expression of the FMS receptor and ligand (CSF-1). Therefore, while ITD mutations were not found, the findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation.
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PMID:Lack of KIT or FMS internal tandem duplications but co-expression with ligands in AML. 1468 12


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