Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to p21(ras) (Ras) and other signaling molecules. Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies. We analyzed specimens from 278 pediatric patients with acute myelogenous leukemia (AML) who were enrolled on Children's Cancer Group trials 2941 and 2961 for PTPN11 mutations. Missense mutations of PTPN11 were detected in 11 (4%) of these samples. None of these patients had mutations in NRAS; however, one patient had evidence of a FLT3 alteration. Four of the patients with PTPN11 mutations (36%) were boys with French-American-British (FAB) morphology M5 AML (P=0.012). Patients with mutations also presented with elevated white blood cell counts. There was no difference in clinical outcome for patients with and without PTPN11 mutations. These characteristics identify a subset of pediatric AML with PTPN11 mutations that share clinical and biologic features with JMML.
Leukemia 2004 Nov
PMID:PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. 1538 33

We explored the relationship of RAS gene mutations with epidemiologic and cytogenetic factors in a case series of children with leukemia. Diagnostic bone marrow samples from 191 incident leukemia cases from the Northern California Childhood Leukemia Study were typed for NRAS and KRAS codon 12 and 13 mutations. A total of 38 cases (20%) harbored RAS mutations. Among the 142 B-cell acute lymphoblastic leukemia (ALL) cases, RAS mutations were more common among Hispanic children (P=0.11) or children born to mothers <30 years (P=0.007). Those with hyperdiploidy at diagnosis (>50 chromosomes) had the highest rates of RAS mutation (P=0.02). A multivariable model confirmed the significant associations between RAS mutation and both maternal age and hyperdiploidy. Interestingly, smoking of the father in the 3 months prior to pregnancy was reported less frequently among hyperdiploid leukemia patients than among those without hyperdiploidy (P=0.02). The data suggest that RAS and high hyperdiploidy may be cooperative genetic events to produce the leukemia subtype; and furthermore, that maternal age and paternal preconception smoking or other factors associated with these parameters are critical in the etiology of subtypes of childhood leukemia.
Leukemia 2005 Mar
PMID:RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia. 1567 22

Severe congenital neutropenia (CN) is characterized by a maturation arrest of myelopoiesis at the promyelocyte stage. Treatment with pharmacological doses of recombinant human granulocyte colony-stimulating factor (rh-G-CSF) stimulates neutrophil production and decreases the risk of major infectious complications. However, approximately 15% of CN patients develop myeloid malignancies that have been associated with somatic mutations in the G-CSF receptor (G-CSFR) and RAS genes as well as with acquired monosomy 7. We report a CN patient with chronic myelomonocytic leukemia (CMML) who never received rh-G-CSF. Molecular analysis demonstrated a somatic G-CSFR mutation (C2390T), which led to expression of a truncated G-CSFR protein in the CMML. Normal G-CSFR expression was unexpectedly absent in primary and cultured CMML. In addition, CMML cells showed monosomy 7 and an oncogenic NRAS mutation. In vitro culture revealed a G-CSF-dependent proliferation of CMML cells, which subsequently differentiated along the monocytic/macrophage lineage. Our results provide direct evidence for the in vivo expression of a truncated G-CSFR in leukemic cells, which emerged in the absence of rh-G-CSF treatment and transduces proliferative signals.
Leukemia 2005 Apr
PMID:An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia. 1572 85

Recently, somatic mutations of the nucleophosmin gene (NPM1), which alter the subcellular localization of the product, have been reported in acute myeloid leukemia (AML). We analyzed the clinical significance of NPM1 mutations in comparison with cytogenetics, FLT3, NRAS, and TP53 mutations, and a partial tandem duplication of the MLL gene (MLL-TD) in 257 patients with AML. We found NPM1 mutations, including 4 novel sequence variants, in 64 of 257 (24.9%) patients. NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations. In 190 patients without the M3 French-American-British (FAB) subtype who were treated with the protocol of the Japan Adult Leukemia Study Group, multivariate analyses showed that the NPM1 mutation was a favorable factor for achieving complete remission but was associated with a high relapse rate. Sequential analysis using 39 paired samples obtained at diagnosis and relapse showed that NPM1 mutations were lost at relapse in 2 of the 17 patients who had NPM1 mutations at diagnosis. These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy.
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PMID:Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. 1599 85

Activating mutations in RAS and receptor tyrosine kinases such as KIT and FLT3 are hypothesized to cooperate with chimeric transcription factors in the pathogenesis of acute myeloid leukemia (AML). To test this hypothesis, we genotyped 150 pediatric AML samples for mutations in KIT (exons 8, 17), NRAS and KRAS (exons 1, 2) and FLT3/ITD. This is the largest cohort of pediatric AML patients reported thus far screened for all four mutations. Of the children with AML, 40% had a mutation in KIT (11.3%), RAS (18%) or FLT3/ITD (11.1%), and 70% of cases of core-binding factor (CBF) leukemia were associated with a mutation of KIT or RAS. Mutations in RAS or FLT3/ITD were frequently found in association with a normal karyotype. Patients with a FLT3/ITD mutation had a significantly worse clinical outcome. However, the presence of a KIT or RAS mutation did not significantly influence clinical outcome. We demonstrate that KIT exon 8 mutations result in constitutive ligand-independent kinase activation that can be inhibited by clinically relevant concentrations of imatinib. Our results demonstrate that abnormalities of signal transduction pathways are frequent in pediatric AML. Future clinical studies are needed to determine whether selective targeting of these abnormalities will improve treatment results.
Leukemia 2005 Sep
PMID:Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. 1601 87

The molecular characterization of leukemia has demonstrated that genetic alterations in the leukemic clone frequently fall into 2 classes, those affecting transcription factors (e.g., AML1-ETO) and mutations affecting genes involved in signal transduction (e.g., activating mutations of FLT3 and KIT). This finding has favored a model of leukemogenesis in which the collaboration of these 2 classes of genetic alterations is necessary for the malignant transformation of hematopoietic progenitor cells. The model is supported by experimental data indicating that AML1-ETO and FLT3 length mutation (FLT3-LM), 2 of the most frequent genetic alterations in AML, are both insufficient on their own to cause leukemia in animal models. Here we report that AML1-ETO collaborates with FLT3-LM in inducing acute leukemia in a murine BM transplantation model. Moreover, in a series of 135 patients with AML1-ETO-positive AML, the most frequently identified class of additional mutations affected genes involved in signal transduction pathways including FLT3-LM or mutations of KIT and NRAS. These data support the concept of oncogenic cooperation between AML1-ETO and a class of activating mutations, recurrently found in patients with t(8;21), and provide a rationale for therapies targeting signal transduction pathways in AML1-ETO-positive leukemias.
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PMID:The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. 1602 55

In the present study 170 newly diagnosed acute promyelocytic leukaemia patients (M3: n = 121; M3v: n = 49) were molecularly characterised with respect to PML breakpoint and additional molecular mutations. In total, 83 patients were positive for bcr1 (49%), five for bcr2 (3%) and 82 for bcr3 (48%). Bcr3 was more frequent in M3v (65.3%) compared with M3 (41.3%) (P = 0.005). Cases with bcr3 showed a significantly higher white blood cell count (median: 3.65 x 10(9)/l vs. 1.59 x 10(9)/l, P = 0.003), as well as a higher PML-RARAABL expression ratio (14.8% vs. 72.7%, P < 0.005) compared with bcr1. FLT3-length-mutations were detected more frequently together with bcr3 compared with bcr1 (56.5% vs. 19.4%, P < 0.001) and in M3v compared with M3 (64.5% vs. 24.1%, P < 0.005). FLT3 tyrosine kinase mutations were found in eight cases (6.4%) and were distributed equally within the total group. Analysis for further mutations revealed no MLL-PTD and KIT mutations and only two cases of 99 analysed (2%) with NRAS mutations. FLT3-mutations were detected in 62 of 139 cases (44.6%) and associated with a significant lower overall survival (P = 0.0339). In addition, cases with bcr3 showed a tendency for a worse event-free survival (P = 0.0795) compared with the bcr1 group.
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PMID:Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. 1602 47

Knowledge of the molecular events that govern human thyroid tumorigenesis has grown considerably in the past ten years. Key genetic alterations and new oncogenic pathways have been identified. Molecular genetic aberrations in thyroid carcinomas bear noteworthy resemblance to those in acute myelogenous leukemias. Thyroid carcinomas and myeloid leukemias both possess transcription factor gene rearrangements-PPARgamma-related translocations in thyroid carcinoma and RARalpha-related and CBF-related translocations (amongst others) in myeloid leukemia. PPARgamma and RARalpha are closely related members ofthe same nuclear receptor subfamily, and the PML-RARalpha and PAX8-PPARgamma fusion proteins both function as dominant negative inhibitors of their wild-type parent proteins. Thyroid carcinomas and myeloid leukemias also both harbor NRAS mutations (15-25% of both cancers) and receptor tyrosine kinase mutations--RET mutations in thyroid carcinomas and FLT3 mutations in myeloid leukemias. The NRAS and tyrosine receptor kinase mutations are not observed in the same thyroid carcinoma or leukemia patients, suggesting that multiple initiating pathways exist in both. Lastly, thyroid carcinomas and myeloid leukemias possess p53 mutations at relatively low frequency (10-15%) in patients who tend to be older and have more aggressive, therapy resistant disease. Such parallels are unlikely to occur by chance alone and argue that common mechanisms underlie these diverse epithelial and hematologic cancers. The comparison of thyroid carcinomas and myeloid leukemias may highlight areas of thyroid cancer investigation worthy of further focus. For example, few collaborating mutations have been defined in thyroid carcinomas even though they play a clear role in myeloid leukemias, as exemplified by RARalpha rearrangements and FLT3 mutations that together dictate the promyleocytic leukemia phenotype. Functional interactions between collaborating mutations are possible at multiple levels, and it is tempting to speculate that some thyroid carcinomas might develop through an unique combination or co-activation of RET and RAS and/or RET and PPARgamma (and/or other) signaling systems. In fact, the ELE1-RET (PTC3) fusion protein contains the ELE1 nuclear receptor co-activator domain and it appears to physically associate with and inhibit wild-type PPARgamma in some papillary carcinomas. The similarities of the fusion proteins in thyroid carcinoma and myeloid leukemia suggest that a more directed search for fusion genes in non-thyroid carcinomas is warranted. In fact, novel fusion genes have been identified recently in aggressive midline, secretory breast, and renal cell carcinomas, although the epithelial nature of the latter is not well-documented. Interestingly, these cancers all tend to present more frequently in adolescence and young adulthood in a manner similar to thyroid and myeloid malignancies that have fusion genes. The analyses of cancers that present earlier in life may enhance fusion gene recognition in other carcinoma types. Definition and biologic characterization of the precursor cells that give rise to thyroid carcinoma will also be important. Myeloid leukemias are thought to arise from stem/progenitor cells that acquire disturbed self-renewal and differentiation capacities but retain characteristics of the myeloid lineages. Although the presence of comparable stem/progenitor cells in the thyroid are not defined, distinct thyroid cancer lineages and patterns of differentiation exist and candidate stem/progenitor cells such as the p63-immunoreactive solid cell nests are apparent. A last important area is development of molecular-based therapies for thyroid carcinoma patients resistant to standard radio-iodine treatment. Treatments for such cancers are limited and pathways defined by thyroid cancer mutations are prime targets for pharmacologic interventions with molecular inhibitors. Tyrosine kinase inhibitors and nuclear receptor ligands have proven dramatically effective in some myeloid leukemia patients. Various molecular inhibitors are being investigated now in thyroid cancer models. Such developments predict that the thyroid cancer model will continue to provide biologic insights into human carcinoma biology and that improved pathologic diagnosis and treatment for thyroid cancer patients sit on the not too distant horizon.
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PMID:Molecular events in follicular thyroid tumors. 1620 39

Mutations in codon D816 of the KIT gene represent a recurrent genetic alteration in acute myeloid leukemia (AML). To clarify the biologic implication of activation loop mutations of the KIT gene, 1940 randomly selected AML patients were analyzed. In total, 33 (1.7%) of 1940 patients were positive for D816 mutations. Of these 33 patients, 8 (24.2%) had a t(8;21), which was significantly higher compared with the subgroup without D816 mutations. Analyses of genetic subgroups showed that KIT-D816 mutations were associated with t(8;21)/AML1-ETO and other rare AML1 translocations. In contrast, other activating mutations like FLT3 and NRAS mutations were very rarely detected in AML1-rearranged leukemia. KIT mutations had an independent negative impact on overall (median 304 vs 1836 days; P = .006) and event-free survival (median 244 vs 744 days; P = .003) in patients with t(8;21) but not in patients with a normal karyotype. The KIT-D816V receptor expressed in Ba/F3 cells was resistant to growth inhibition by the selective PTK inhibitors imatinib and SU5614 but fully sensitive to PKC412. Our findings clearly indicate that activating mutations of receptor tyrosine kinases are associated with distinct genetic subtypes in AML. The KIT-D816 mutations confer a poor prognosis to AML1-ETO-positive AML and should therefore be included in the diagnostic workup. Patients with KIT-D816-positive/AML1-ETO-positive AML might benefit from early intensification of treatment or combination of conventional chemotherapy with KIT PTK inhibitors.
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PMID:KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. 1625 34

Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P=0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P=0.03), and with a normal karyotype (P=0.004), but inversely associated with previous therapy with alkylating agents (P=0.003) and with -7/7q- (P=0.001). RAS mutations were associated with AML1 point mutations (P=0.046) and with progression from t-MDS to t-AML (P=0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t(9;11)(p22;q23) and MLL-rearrangement (P=0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P=0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted 'class-I' mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted 'class-II' mutations) (P=0.046) suggesting their cooperation in leukemogenesis.
Leukemia 2005 Dec
PMID:Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. 1628 Oct 72


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