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)

This phase 2 pilot study was conducted to determine the efficacy and safety of imatinib mesylate in patients with c-kit-positive acute myeloid leukemia (AML) refractory to or not eligible for chemotherapy. Twenty-one patients were enrolled and received imatinib 600 mg orally once daily. Five responses were seen primarily in patients, starting with relatively low blast counts in bone marrow (BM) and peripheral blood (PB): 2 patients who were considered refractory on chemotherapy on the basis of persistence of blasts in PB and BM met the criteria for complete hematologic remission, 1 patient had no evidence of leukemia, and 2 patients achieved a minor response. Treatment with imatinib demonstrated a good safety profile and was well tolerated. Western blot analysis and immunohistochemistry demonstrated c-Kit activation in primary AML cells. Further, imatinib treatment of primary AML cells inhibited c-Kit tyrosine-phosphorylation. Genomic DNA-sequencing of c-KIT showed no mutations in exons 2, 8, 10, 11, 12, and 17. Although some of the responses derived from relatively small reductions in leukemic blasts and may be attributable, in part, to prior chemotherapy, these cases suggest that imatinib has interesting clinical activity in a subset of patients with c-kit-positive AML. Further clinical trials are warranted to explore the clinical potential of imatinib in AML and to identify the underlying molecular mechanism.
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PMID:Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. 1563 13

Approximately 20% of patients with systemic mastocytosis (SM) have an associated haematological, clonal, non-mast cell lineage disease, and most exhibit an associated myelogenous neoplasm. This report describes a 48 year old man with acute myeloid leukaemia (AML) and a type t(8;21) cytogenetic abnormality. Associated bone marrow mastocytosis (a defined subtype of SM) was only detected after successful polychemotherapy in the state of bone marrow aplasia, and persisted after complete remission of AML. The diagnosis of mastocytosis was based on the demonstration of a multifocal dense mastocytic infiltrate. The atypical mast cells showed prominent spindling and an aberrant immunophenotype, with coexpression of tryptase, chymase, KIT, and CD25-which is expressed only on neoplastic (not normal) mast cells. In addition, the transforming somatic mutation D816V of the c-kit gene was detected. Re-examination of the pretherapeutic (initial) bone marrow revealed a slight diffuse increase in partially spindle shaped mast cells also exhibiting an abnormal immunophenotype, with CD25 expression, although compact mastocytic infiltrates were not detected. Because the D816V mutation was detected in the initial bone marrow specimen, strict application of three minor diagnostic criteria (spindling, CD25, D816V) enabled a diagnosis of SM-AML to be confirmed retrospectively in the initial bone marrow tissue.
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PMID:Acute myeloid leukaemia with t(8;21) associated with "occult" mastocytosis. Report of an unusual case and review of the literature. 1499 Jun 11

Activating FLT3 mutations are the most common genetic aberrations in acute myeloid leukemia (AML), resulting in the constitutive activation of this receptor tyrosine kinase (RTK), but such mutations are rarely found in acute lymphoblastic leukemia (ALL). Here we describe a unique subset of de novo adult T-cell ALL (T-ALL) cases that coexpress CD117/KIT and cytoplasmic CD3 (CD117/KIT(+) ALL). Activating mutations in the FLT3 RTK gene were found in each of 3 CD117/KIT(+) cases that were analyzed, but not in 52 other adult T-ALL samples from the same series that lacked CD117/KIT expression. Our results indicate the need for clinical trials to test the efficacy of drugs that inhibit the FLT3 RTK in this subset of patients with T-ALL.
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PMID:Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. 1632 81

Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
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PMID:Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. 1524 81

It is known that Notch activation promotes the self-renewal of hematopoietic cells. However, we have previously found that the growth of a myeloid leukemia cell line, OCI/AML-6, was suppressed by Notch activation induced by stimulation with a recombinant Notch ligand, Delta-1 protein. We recently found that the growth of another leukemia cell line, THP-1, was also suppressed by the ligands Delta-1 and Jagged-1. In this study, we tried to clarify the cellular and molecular mechanism of the growth suppression induced by Notch activation. Flow cytometric analysis showed that Delta-1 stimulation increased the expression of differentiation markers such as CD11b and CD13 while it decreased the expression of CD117 (c-KIT), a marker for primitive cells in THP-1 cells. In OCI/AML-6 cells, Delta-1 stimulation decreased the expression of CD11b and CD14 and increased CD34 expression. Namely, Delta-1 showed the opposite effects on the differentiation markers of each cell line. Delta-1 stimulation did not increase the binding of annexin V, a marker for apoptotic cells in either cell line. Since the growth of myeloid cells is regulated by MAP kinase and JAK/STAT pathways, we investigated the effects of the ligand stimulation on these pathways. Delta-1 stimulation did not induce the phosphorylation of ERK1/2 and STAT3 proteins in either cell line. Pre-exposure to Delta-1 did not affect the phosphorylation of ERK1/2 and STAT3 induced by G-CSF in OCI/AML-6 cells, either. Namely, it is thought that these pathways are not involved in the growth suppression caused by Notch ligands. Our study revealed several findings on Notch function. However, the precise mechanism remains to be elucidated.
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PMID:Cellular analysis of growth suppression induced by the Notch ligands, Delta-1 and Jagged-1 in two myeloid leukemia cell lines. 1525 69

Oncogenic mutations of the receptor tyrosine kinase KIT occur in gastrointestinal stromal tumors (GISTs), some cases of acute myelogenous leukemia (AML), and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analyzed the inhibitory potential of 2 small molecule inhibitors, MLN518 and PD180970, against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT, and signal transducer and activator of transcription-3 (Stat3) phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase 1 clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations.
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PMID:Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. 1530 88

Acute myeloid leukaemia (AML) has been proposed to arise from the collaboration between two classes of mutation, a class I, or proliferative, mutation and a class II, or blocking, mutation. A limitation of this so-called 'two-hit' hypothesis has been the lack of identifiable proliferative and blocking mutations in most AML cases. However, it is now known that the CBFbeta-MYH11 fusion gene in AML and inv(16), by disrupting the normal transcription factor activity of core binding factor (CBF), functions as a class II mutation. In addition, nearly 70% of patients with AML and inv(16) are known to possess mutually exclusive mutations of the receptor tyrosine kinases (RTKs), c-KIT and FLT3, as well as RAS genes, that provide a class I, or proliferative, signal. AML and inv(16), therefore, is one of the best understood of the acute leukaemias at the genetic level and so provides a paradigm for the 'two-hit' hypothesis of leukaemogenesis. This paper reviews the recent advances in the molecular pathology of AML and inv(16) and discusses possible therapeutic implications of the current pathogenetic model.
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PMID:Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis? 1560 46

KIT exon 8 mutations are located in the extracellular portion of the receptor and are strongly associated with core-binding factor (CBF)-acute myeloid leukemia (AML). To characterize the functional role of these mutants, we analyzed the proproliferative and antiapoptotic potential of 3 KIT exon 8 mutations in interleukin 3 (IL-3)-dependent Ba/F3 cells. All KIT exon 8 mutants induced receptor hyperactivation in response to stem cell factor (SCF) stimulation in terms of proliferation and resistance toward apoptotic cell death. A representative KIT exon 8 mutant showed spontaneous receptor dimerization, phosphorylation of mitogen-activated protein kinase (MAPK), and conferred IL-3-independent growth to Ba/F3 cells. MAPK and phosphatidylinositol 3-kinase (PI3-kinase) activation was essential for the phenotype of this mutant. Additionally, imatinib inhibited proliferation of KIT exon 8 mutant-expressing Ba/F3 cells. Our data show that KIT exon 8 mutations represent gain-of-function mutations and might represent a new molecular target for treatment of CBF leukemias.
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PMID:KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. 1561 74

The Kasumi-1 cell line is an intensively investigated model system of Acute Myeloid Leukemia with t(8;21) translocation, that represents 1 of the 2 main subtypes of Core Binding Factor Leukemia (CBFL). Since establishment in 1991 the Kasumi-1 cell line has provided the tool to study the peculiar molecular, morphologic, immunophenotypic findings of AML with t(8;21) and the functional consequences of the AML1-ETO fusion oncogene on myeloid differentiation. Leukemogenesis involves multiple genetic changes and, as suggested by murine experiments and other findings in humans, AML1-ETO expression may not be sufficient for full blown leukemia. In agreement with the "two hits" model of leukemogenesis, based on the cooperation between 1 class of mutations that impair hematopoietic differentiation and a second class of mutations that confer a proliferative and/or survival advantage to hematopoietic progenitors an activating mutation in the tyrosine kinase domain of the c-kit gene was identified in the AML1/ETO expressing Kasumi-1 cell line. The dosage of the Asn822Lys mutated allele was shown to be about 5-fold compared to the normal allele and c-kit amplification was found to map to minute 4cen-q11 marker chromosomes, likely derived from the extra chromosome 4 recorded in the newly established cell line. The combination of t(8;21) and trisomy 4 leading to enhanced dosage of a mutated kit allele is a feature of a few CBFL patients reproduced by the Kasumi-1 cell model. The Kasumi-1 cell line, paralleling the commitment stage of CBF leukemia also provides a valuable resource to investigate the effect of tyrosine kinase kit mutant on the main KIT-regulated signal transduction pathways, i.e. MAPK, PI3K/AKT and STAT3 and the diverse inhibitory effect exerted by STI 571 on these KIT mutant activated pathways. PI3K-dependent activation of AKT and STAT activation was observed in Kasumi-1 cells. Contrary to the expectations for an amplified tyrosine kinase kit mutant, we found that STI 571 inhibited KIT Asn822Lys tyrosine phosphorylation and downstream JNK and STAT3 effectors in Kasumi-1 cells, but had no effect on constitutive activation of AKT, suggesting that signaling by tyrosine kinases other than KIT may be responsible for its activation in Kasumi-1 cells. Independent findings on the same model system provide complementary insights into designing strategies for treatment of CBF leukemia associated with mutations in the KIT catalytic domain.
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PMID:The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia. 1562 9

To explore the genetic abnormalities that cooperate with AML1-ETO (AE) fusion gene to cause acute myeloid leukemia (AML) with t(8;21), we screened a number of candidate genes and identified 11 types of mutations in C-KIT gene (mC-KIT), including 6 previously undescribed ones among 26 of 54 (48.1%) cases with t(8;21). To address a possible chronological order between AE and mC-KIT, we showed that, among patients with AE and mC-KIT, most leukemic cells at disease presentation harbored both genetic alteration, whereas in three such cases investigated during complete remission, only AE, but not mC-KIT, could be detected by allele-specific PCR. Therefore, mC-KIT should be a subsequent event on the basis of t(8;21). Furthermore, induced expression of AE in U937-A/E cells significantly up-regulated mRNA and protein levels of C-KIT. This may lead to an alternative way of C-KIT activation and may explain the significantly higher C-KIT expression in 81.3% of patients with t(8;21) than in patients with other leukemias. These data strongly suggest that t(8;21) AML follows a stepwise model in leukemogenesis, i.e., AE represents the first, fundamental genetic hit to initiate the disease, whereas activation of the C-KIT pathway may be a second but also crucial hit for the development of a full-blown leukemia. Additionally, Gleevec suppressed the C-KIT activity and induced proliferation inhibition and apoptosis in cells bearing C-KIT N822K mutation or overexpression, but not in cells with D816 mC-KIT. Gleevec also exerted a synergic effect in apoptosis induction with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia.
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PMID:AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. 1565 49


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