Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FLT3 is a class III receptor tyrosine kinase together with KIT, FMS and PDGFR. FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence, and subsequently as a missense mutation of D835 (FLT3/KDM) within a kinase domain. Furthermore, point mutations, deletions, and insertions in the codons surrounding D835 have also been found. FLT3/ITD and FLT3/KDM occur in 15% to 35% and 5% to 10%, respectively, of patients with AML. FLT3 mutations are, therefore, the most frequent genetic alterations so far reported in AML. Several large-scale studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis. Although the clinical significance of FLT3/KDM is controversial, the meta-analysis suggests its adverse effect on the outcome. FLT3/ITD is far less common in patients with ALL, whereas FLT3/KDM is recurrently found in patients with ALL, especially in those harboring an MLL gene rearrangement or hyperdiploidy. The overexpression of FLT3 transcripts has been demonstrated in a pro-portion of the AML patients without FLT3 mutations, which are associated with a poor prognosis for overall survival. Routine screening of FLT3 mutations is recommended to stratify the patients into distinct risk groups, while the optimal treatment strategy for patients with FLT3 mutations should be further evaluated.
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PMID:Clinical significance of FLT3 in leukemia. 1614 37

Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1*B genotype against the development of t-leuk/MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.
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PMID:Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients. 1616 58

AG-013736 is an oral anti-angiogenesis agent with activity against a variety of receptor tyrosine kinases, including VEGFR-1, VEGFR-2, VEGFR-3, c-kit, and PDGFR-beta. A phase 2 study was conducted in patients with poor prognosis AML or MDS. Twelve patients (six AML; six MDS) were treated with AG-013736 at a dose of 10mg orally daily for a median of 56 days (range, 1-248 days). Median age was 80 years (range, 58-88 years). Grade 3 or 4 drug-related toxicities included hypertension (42%), mucositis (8%) and deep venous thrombosis (8%). No objective responses occurred; two patients with MDS had stable disease for 8.3 and 6.2 months, respectively. Bone marrow expression of VEGFR-1 and VEGFR-2 was observed in 11% and 0% of patients, respectively. Sustained decreases in soluble VEGFR-2 plasma levels with concomitant elevation in plasma VEGF and placental growth factor levels were obtained during the course of therapy with AG-013736. AG-01736 had minimal biologic or clinical activity in this elderly patient population.
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PMID:The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). 1633 90

We analyzed 2502 patients with acute myeloid leukemia at diagnosis for NRAS mutations around the hot spots at codons 12, 13, and 61 and correlated the results to cytomorphology, cytogenetics, other molecular markers, and prognostic relevance of these mutations. Two hundred fifty-seven (10.3%) of 2502 patients had NRAS mutations (NRAS(mut)). Most mutations (112 of 257; 43.6%) were found at codon 12, mostly resulting in changes from glycine to asparagine. The history of AML did not differ significantly in association with NRAS mutations. The subgroups with inv(16)/t(16;16) and inv(3)/t(3;3) showed a significantly higher frequency of NRAS(mut) (50 of 133, 37.6% [P < .001], and 11 of 41, 26.8% [P = .004], respectively) than the total cohort. In addition, in these 2 subgroups, mutations of codon 61 were significantly overrepresented (both P < .001). In contrast, NRAS mutations were significantly underrepresented in t(15;17) (2 of 102; 2%; P = .005) in the subgroup with MLL/11q23 rearrangements (3 of 77; 3.9%; P = .061) and in the complex aberrant karyotype (4 of 258; 1.6%; P < .001). Overall, we did not find a significant prognostic impact of NRAS(mut) for overall survival, event-free survival, and disease-free survival. However, there was a trend to better survival in most subgroups, especially when other molecular markers (FLT3-LM, MLL-PTD, and NPM) were taken into account.
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PMID:Implications of NRAS mutations in AML: a study of 2502 patients. 1643 92

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with -7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of -5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P < 0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with -7/7q- alteration, and frequently involves RTK-RAS signaling pathway activation.
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PMID:Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. 1646 64

The progenitor cells of myelodysplastic syndrome (MDS) are thought to undergo a multistep process during their transformation into overt acute leukemia. In this study, the role of mutation of the KIT gene in the extracellular membrane, juxtamembrane and tyrosine kinase domains was investigated in 75 patients with MDS or MDS-derived leukemia (MDS-AML). Mutation was detected in 2 of 15 (13.3%) patients with refractory anemia with excess blasts transformation (RAEB-T), in 1 of 15 (6.6%) patients with chronic myelomonocytic leukemia (CMML), and in 5 of 26 (19.2%) patients with MDS-AML. However, no mutation was found in any of the nine patients with refractory anemia (RA) or the 10 patients with refractory anemia with excess blasts (RAEB). Of the mutations, five patients had changes at the same codon in tyrosine kinase domain, Asp816, while the remainder had unique mutations. These observations suggest that KIT gene mutations identified in the advanced stage of MDS, and genetic abnormality in the KIT gene, particularly at codon 816, might be additional events that contribute to the progression of MDS to AML.
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PMID:Mutational analysis of the KIT gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. 1653 29

Previous studies have shown that activation of the signal transducer and activator of transcription 5 (STAT5) plays an essential role in leukemogenesis mediated through constitutive activated protein tyrosine kinases (PTK). Because PIM-1 is a STAT5 target gene, we analyzed the role of the family of PIM serine/threonine kinases (PIM-1 to PIM-3) in PTK-mediated transformation of hematopoietic cells. Ba/F3 cells transformed to growth factor independence by various oncogenic PTKs (TEL/JAK2, TEL/TRKC, TEL/ABL, BCR/ABL, FLT3-ITD, and H4/PDGFbetaR) show abundant expression of PIM-1 and PIM-2. Suppression of PIM-1 activity had a negligible effect on transformation. In contrast, expression of kinase-dead PIM-2 mutant (PIM-2KD) led to a rapid decline of survival in Ba/F3 cells transformed by FLT3-ITD but not by other oncogenic PTKs tested. Coexpression of PIM-1KD and PIM-2KD abrogated growth factor-independent growth of Ba/F3 transformed by several PTKs, including BCR/ABL. Targeted down-regulation of PIM-2 by RNA interference (RNAi) selectively abrogated survival of Ba/F3 cells transformed by various Fms-like tyrosine kinase 3 (FLT3)-activating mutants [internal tandem duplication (ITD) and kinase domain] and attenuated growth of human cell lines containing FLT3 mutations. Interestingly, cells transformed by FLT3 and BCR/ABL mutations that confer resistance to small-molecule tyrosine kinase inhibitors were still sensitive to knockdown of PIM-2, or PIM-1 and PIM-2 by RNAi. Our observations indicate that combined inactivation of PIM-1 and PIM-2 interferes with oncogenic PTKs and suggest that PIMs are alternative therapeutic targets in PTK-mediated leukemia. Targeting the PIM kinase family could provide a new avenue to overcome resistance against small-molecule tyrosine kinase inhibitors.
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PMID:Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor-sensitive and kinase inhibitor-resistant forms of Fms-like tyrosine kinase 3 and BCR/ABL. 1658 10

Point mutations of AML1 are uncommon and predominantly reported in a rare minimally differentiated acute myeloid leukemia (M0 AML). Few data exist regarding the frequency of AML1 mutations in non-M0 cases. We screened 284 consecutive adult Thai patients with de novo AML and found that 3.9% had AML1 mutations. The highest incidence occurred in M6. Six novel mutations were uniquely identified in non-M0 cases. Sixty-four percent of the non-M0 patients with AML1 mutations had coexisting genetic abnormalities including FLT3 mutation in 36%. Our study provides evidence to support the model of multiple co-operating events, which could also be critical in the development of leukemia in non-M0 AML patients with mutated AML1. The prognostic significance of these novel mutations remains to be determined.
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PMID:Mutations of AML1 in non-M0 acute myeloid leukemia: six novel mutations and a high incidence of cooperative events in a South-east Asian population. 1662 49

In systemic mastocytosis with associated clonal, hematological non-mast cell lineage disease (SM-AHNMD), mast cell infiltration of the bone marrow coexists with a hematologic neoplasm, usually of myeloid origin. Activating KIT gene mutations are universally present in these neoplastic mast cells. When SM is associated with AML, the leukemic cells commonly carry the t(8;21)(q22;q22) core binding factor translocation. The precise relationship between neoplastic mast cells and the leukemic clone has remained unclear. By target FISH analysis, we demonstrate t(8;21) in the bone marrow mast cells of a patient with systemic mastocytosis associated with t(8;21) AML, thus, proving the origin of these neoplastic mast cells from the leukemic clone. We also show that after successful allogeneic hematopoietic stem cell transplantation, these neoplastic bone marrow mast cells can persist without adverse consequences and gradually decline with time.
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PMID:Neoplastic mast cells in systemic mastocytosis associated with t(8;21) acute myeloid leukemia are derived from the leukemic clone. 1687 62

Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases, VEGFR-1 and VEGFR-2, are important therapeutic targets for various cancers including AML. Paraffin-embedded bone marrow samples (PE-BM) are, in most cases, the only tissue accessible to perform retrospective analyses of novel targets such as VEGF and/or its receptors. As a result, it limits our options to immunohistochemistry (IHS), or more expensive and less practical techniques such as enzyme-linked immunosorbent assay (ELISA) or fluorescence in situ hybridization (FISH). We analyzed the feasibility of IHS to measure VEGFR-1 and VEGFR-2 expression in 28 AML samples using monoclonal antibodies (moAbs) against Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). Medical records were reviewed for relevant clinical information. Expression of VEGFR-1 (+) and VEGFR-2 (+) were seen in 25% (7/28) and 43% (12/28) respectively. Forty-six percent (13/28) were dual-negatives for VEGFR-1 and VEGFR-2; 14% (4/28) were dual-positives for VEGFR-1 and VEGFR-2. An inferior survival was observed in patients whose myeloblasts express either VEGFR-1 (+) or VEGFR-2 (+), or both. Determination of expression of VEGF receptors (1 and 2) by IHS in PE-BM tissue is feasible. Prospective comparison of IHC to flow cytometry or other molecular techniques, and assessment of the prognostic significance of VEGF receptors in AML patients is warranted.
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PMID:Expression of the vascular endothelial growth factor receptors 1 and 2 in acute myeloid leukemia: incidence and feasibility of immunohistochemical staining. 1689 65


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