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)

Oncogenic activation loop KIT mutations are observed in acute myeloid leukemia (AML) and systemic mastocytosis (SM); however, unlike the KIT juxtamembrane mutants, the activation loop mutants are insensitive to imatinib mesylate. Furthermore, as prior studies primarily used heterologous cell lines, the molecular mechanism(s) underlying oncogenic KIT-induced transformation in primary cells is poorly understood. We demonstrate that expression of KITD814V in primary hematopoietic stem/progenitor cells (HSC/Ps) and mast cell progenitors (MCps) induces constitutive KIT autophosphorylation, supports ligand-independent hyperproliferation, and promotes promiscuous cooperation with multiple cytokines. Genetic disruption of p85 alpha, the regulatory subunit of class IA lipid kinase phosphoinositol-3-kinase (PI3K), but not of p85 beta, or genetic disruption of the hematopoietic cell-specific Rho GTPase, Rac2, normalizes KITD814V-induced ligand-independent hyperproliferation. Additionally, deficiency of p85 alpha or Rac2 corrects the promiscuous hyperproliferation observed in response to multiple cytokines in both KITD814V-expressing HSC/Ps and MCps. Treatment of KITD814V-expressing HSC/Ps with a Rac inhibitor (NC23766) or with rapamycin showed a dose-dependent suppression in ligand-independent growth. Taken together, our results identify p85 alpha and Rac2 as potential novel therapeutic targets for the treatment of KITD814V-bearing AML and SM.
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PMID:Genetic and pharmacologic evidence implicating the p85 alpha, but not p85 beta, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis. 1748 98

AML1/RUNX1 is implicated in leukemogenesis on the basis of the AML1-ETO fusion transcript as well as somatic mutations in its DNA-binding domain. Somatic mutations in RUNX1 are preferentially detected in acute myeloid leukemia (AML) M0, myeloid malignancies with acquired trisomy 21, and certain myelodysplastic syndrome (MDS) cases. By correlating the presence of RUNX1 mutations with cytogenetic and molecular aberration in a large cohort of AML M0 (N = 90) at diagnosis, we detected RUNX1 mutations in 46% of cases, with all trisomy 13 cases (n = 18) being affected. No mutations of NRAS or KIT were detected in the RUNX1-mutated group and FLT3 mutations were equally distributed between RUNX1-mutated and unmutated samples. Likewise, a high incidence of RUNX1 mutations (80%) was detected in cases with trisomy 13 from other French-American-British (FAB) subgroups (n = 20). As FLT3 is localized on chromosome 13, we hypothesized that RUNX1 mutations might cooperate with trisomy 13 in leukemogenesis by increasing FLT3 transcript levels. Quantitation of FLT3 transcript levels revealed a highly significant (P < .001) about 5-fold increase in AML with RUNX1 mutations and trisomy 13 compared with samples without trisomy 13. The results of the present study indicate that in the absence of FLT3 mutations, FLT3 overexpression might be a mechanism for FLT3 activation, which cooperates with RUNX1 mutations in leukemogenesis.
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PMID:Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. 1748 49

Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biologic and clinical heterogeneity within these cytogenetic groups that is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n = 93) of AML patients with CBF leukemia [(inv (16), n = 55; t(8;21), n = 38)]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n = 35) characterized by shorter overall survival times (P = .03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21) subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P = .011 and P = .026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the "favorable" CBF leukemias, antiapoptotic mechanisms and deregulated mTOR signaling and, in the newly defined "unfavorable" subgroup, aberrant MAPK signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biologic basis for the heterogeneity observed in CBF leukemia.
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PMID:Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. 1748 51

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.
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PMID:Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia. 1749 58

We report the case of an infant with acute myeloblastic leukemia who had the abnormal karyotype 46,XX,t(2;11;9)(q31;p15;q22),t(6;11;15)(q21;q23;q22),t(8;10)(q13;q22). At relapse, a different three-way translocation emerged. Fluorescence in situ hybridization and a reverse transcription-polymerase chain reaction assay detected the NUP98-HOXD13 fusion gene in bone marrow cells of the patient at diagnosis and at relapse. Sequence analysis showed that exon 12 of NUP98 was fused in-frame with exon 2 of HOXD13. The patient had neither a rearrangement of the MLL gene nor aberrations for FLT3, KIT, NRAS, KRAS, or PTPN11. The NUP98-HOXD13 fusion transcript created by t(2;11;9)(q31;p15;q22) may play an important role in the leukemogenesis in this case.
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PMID:A complex karyotype, including a three-way translocation generating a NUP98-HOXD13 transcript, in an infant with acute myeloid leukemia. 1765 57

Translocation (8; 21)/AML1-ETO is considered a favorable cytogenetic abnormality in acute myeloid leukemia (AML). However, associated KIT activating mutations confer poor outcome. The immunophenotype associated with KIT mutations in AML1-ETO has not previously been elucidated. We retrospectively reviewed the immunophenotype by flow cytometry of 56 cases of AML with t(8; 21) and compared them with 100 cases of AML without t(8; 21). In 21 t(8; 21) cases, we sought KIT mutations by direct sequencing. Although CD19 and CD56 were aberrantly expressed in 42 (75%) of 56 and 46 (82%) of 56 cases, respectively, with t(8; 21), these markers were only expressed in 4% and 25%, respectively, without t(8; 21) (P < .001). However, the 5 KIT-mutated cases (D816H, 3; D816Y, 1; and N822K, 1) of t(8; 21) AML had diminished CD19 expression (P = .04) with definite CD56 expression (P = .30) on myeloid blasts. Our study suggests that KIT activating mutations in AML with t(8; 21) are associated with diminished CD 19 and positive CD56 expression on leukemic blasts and, thus, can be phenotypically distinguished from AML1-ETO leukemias without KIT mutations.
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PMID:Immunophenotypic profile predictive of KIT activating mutations in AML1-ETO leukemia. 1787 4

c-KIT mutations have been described in core-binding factor (CBF) acute myeloid leukemia (AML) at diagnosis. The role of c-KIT mutations in the relapse of CBF-AML is not clear. The role of CSF1R mutation in the pathogenesis of AML remains to be determined. We analyzed receptor tyrosine kinases (RTKs) and Ras mutations on 154 children with AML. Also, we examined the paired diagnosis and relapse samples in CBF-AML. CBF-AML accounted for 27% (41/154). c-KIT mutations were detected in 41.5% of CBF-AML at diagnosis (6 in exon 8, 10 in exon 17 and 1 in both exons 8 and 17) , FLT3-TKD 2.7%, N-Ras mutations 7.3% and K-Ras mutations 4.9%. FLT3-LM and CSF1R mutations were not found in CBF-AML. The mutations of RTKs and Ras were mutually exclusive except for one patient who had both c-KIT and N-Ras mutations. Eight of the 41 CBF-AML patients relapsed; four patients retained the identical c-KIT mutation patterns as those at diagnosis, the remaining four without c-KIT mutations at diagnosis did not acquire c-KIT mutations at relapse. Our study showed that 54% of childhood CBF-AML had RTKs and/or Ras mutations; c-KIT but not CSF1R mutations play a role in the leukemogenesis of childhood CBF-AML.
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PMID:Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. 1796 Jan 71

The inversion of chromosome 16 in the inv(16)(p13q22) is one of the most frequent cytogenetic abnormalities observed in acute myeloid leukemia (AML). The inv(16) fuses the core binding factor (CBF) beta subunit with the coiled-coil rod domain of smooth muscle myosin heavy chain (SMMHC). Expression of CBFbeta-SMMHC in mice does not promote AML in the absence of secondary mutations. Patient samples with the inv(16) also possess mutually exclusive activating mutations in either N-RAS, K-RAS, or the receptor tyrosine kinases, c-KIT and FLT3, in almost 70% of cases. To test whether an activating mutation of FLT3 (FLT3-ITD) would cooperate with CBFbeta-SMMHC to promote AML, we coexpressed both mutations in hematopoietic progenitor cells used to reconstitute lethally irradiated mice. Analysis of transplanted animals showed strong selection for CBFbeta-SMMHC/FLT3-ITD-expressing cells in bone marrow and peripheral blood. Compared with animals transplanted with only CBFbeta-SMMHC-expressing cells, FLT3-ITD further restricted early myeloid differentiation and promoted peripheralization of primitive myeloblasts as early as 2.5 weeks after transplantation. FLT3-ITD also accelerated disease progression in all CBFbeta-SMMHC/FLT3-ITD-reconstituted animals, which died of a highly aggressive and transplantable AML within 3 to 5 months. These results indicate that FLT3-activating mutations can cooperate with CBFbeta-SMMHC in an animal model of inv(16)-associated AML.
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PMID:FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia. 1796 43

The heterogeneity of acute myeloid leukemia (AML) has been established by many new insights from molecular biological studies. In AML with favorable cytogenetic changes, KIT gene mutation has been known as a worse prognostic marker. Even in AML with normal cytogenetics, numerous molecular genetic alterations have been identified including internal tandem duplication of the FLT3 gene (FLT3-ITD), mutations in the NPM1 gene, mutations in the CEBPA gene, and partial tandem duplication of the MLL gene. Of these, FLT3-ITD has the most important prognostic implication. Insights into the molecular pathogenesis of AML have led to the development of more specific targeted agents. Currently, a number of agents have been explored in AML, including immunoconjugate of anti-CD33 antibody and cytotoxic agent (gemtuzumab ozogamicin: GO), tyrosine kinase inhibitors and farnesyl transferase inhibitor. These agents have shown promise in small studies. Large phase III studies will reveal whether these are effective in inducing complete remission and prolonging survival. Combining targeted agents with each other or with chemotherapy may improve the response rates. GO is the most promising drug, which has been evaluated in randomized trials by several major cooperative groups to determine whether the addition of GO improves the complete remission rate and overall survival. In the near future AML may be classified and treated by their molecular biological alterations.
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PMID:[Acute myeloid leukemia]. 1807 16

Traditional cytotoxic chemotherapy is effective at temporizing AML in the majority of patients but cures a small minority. Thus, enrollment in clinical trials remains a recommended approach for nearly all patients. While signal transduction inhibition is a promising area to advance AML therapy, no agent as monotherapy has demonstrated obvious clinical benefit over traditional cytotoxic chemotherapy. Tipifarnib is perhaps an exception as it is the only signal transduction inhibitor in AML that reproducibly shows clinical benefit using traditional chemotherapy response criteria. Due to toxicity and low response rates, however, the potential advantages of tipifarnib over either traditional cytotoxic chemotherapy or best supportive care alone await confirmation from phase III studies. Available data suggest that combining signal transduction inhibitors with chemotherapy will improve response rates. Clinical trials to test this hypothesis are ongoing using various agents directed against targets such as FLT3, ras/raf/MAPK, mTOR, KIT, and VEGF, but the optimal approach is yet to be defined. Similarly unclear is the benefit of a potent specific kinase inhibitor versus a broad inhibitor of multiple kinases that could prove relevant to leukemia biology. In general, the incomplete understanding of many signal transduction inhibitors' true mechanism of action limits our ability to identify pretreatment predictors of response. To this end, the extensive measures applied to correlate the biologic activity of FLT3 inhibitors with clinical responses are noteworthy and provide useful lessons for clinical trial design and drug development both in leukemia and other cancers.
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PMID:Exploiting signal transduction pathways in acute myelogenous leukemia. 1809 42


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