Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D03343 (MDS)
 2,225 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While a majority of patients with refractory anemia with ring sideroblasts and thrombocytosis harbor JAK2V617F and rarely MPLW515L, JAK2/MPL-negative cases constitute a diagnostic problem. 23 RARS-T cases were investigated applying immunohistochemical phospho-STAT5, sequencing and SNP-A-based karyotyping. Based on the association of TET2/ASXL1 mutations with MDS/MPN we studied molecular pattern of these genes. Two patients harbored ASXL1 and another 2 TET2 mutations. Phospho-STAT5 activation was present in one mutated TET2 and ASXL1 case. JAK2V617F/MPLW515L mutations were absent in TET2/ASXL1 mutants, indicating that similar clinical phenotype can be produced by various MPN-associated mutations and that additional unifying lesions may be present in RARS-T.
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PMID:Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations. 2033 14

Chronic myelomonocytic leukaemia (CMML) is a haematological disease currently classified in the category of myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) because of its dual clinical and biological presentation. The molecular biology of CMML is poorly characterized. We studied a series of 53 CMML samples including 31 cases of myeloproliferative form (MP-CMML) and 22 cases of myelodysplastic forms (MD-CMML) using array-comparative genomic hybridisation (aCGH) and sequencing of 13 candidate genes including ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, PTPN11, RUNX1, TET2 and WT1. Mutations in ASXL1 and in the genes associated with proliferation (CBL, FLT3, PTPN11, NRAS) were mainly found in MP-CMML cases. Mutations of ASXL1 correlated with an evolution toward an acutely transformed state: all CMMLs that progressed to acute phase were mutated and none of the unmutated patients had evolved to acute leukaemia. The overall survival of ASXL1 mutated patients was lower than that of unmutated patients.
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PMID:ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. 2088 Jan 16

TET2 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies including MDS, CMML, MPN, and AML. However, little is known regarding the biological function of TET2 and its role in the pathogenesis of myeloid malignancies. To study the function of TET2 in vivo, we generated a Tet2 knock out mouse model. Deletion of Tet2 in mice led to dramatic reduction in the 5-hydroxymethylcytosine levels and concomitant increase in the 5-methylcytosine levels in the genomic DNA of BM cells. The Tet2(-/-) mice contained an increased Lin(-)Sca-1(+)c-Kit(+) (LSK) cell pool before the development of myeloid malignancies. A competitive reconstitution assay revealed that Tet2(-/-) LSK cells had an increased hematopoietic repopulating capacity with an altered cell differentiation skewing toward monocytic/granulocytic lineages. Approximately 1/3 of Tet2(-/-) and 8% of Tet2(+/-) mice died within 1 year of age because of the development of myeloid malignancies resembling characteristics of CMML, MPD-like myeloid leukemia, and MDS. Furthermore, transplantation of Tet2(-/-), but not wild-type (WT) or Tet2(+/-) BM cells, led to increased WBC counts, monocytosis, and splenomegaly in WT recipient mice. These data indicate that Tet2-deficient mice recapitulate patients with myeloid malignancies, implying that Tet2 functions as a tumor suppressor to maintain hematopoietic cell homeostasis.
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PMID:Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. 2203 42

Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) are distinct, yet related, entities of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) characterized by morphologic dysplasia with accumulation of monocytes or neutrophils, respectively. Our understanding of the molecular pathogenesis of CMML and aCML has advanced, mainly due to the application of novel technologies such as array-based karyotyping and next-generation sequencing. In addition to previously known recurrent aberrations, somatic uniparental disomy affecting chromosomes 3, 4, 7, and 11 frequently occurs in CMML. Novel somatic mutations of genes, including those associated with proliferation signaling (CBL, RAS, RUNX1, JAK2 (V617F)) and with modification of epigenetic status (TET2, ASXL1, UTX, EZH2) have been found. Various combinations of mutations suggest a multistep pathogenesis and may account for clinical heterogeneity. Most recently, several spliceosome-associated-gene mutations were reported and SRSF2 mutations are frequently detected in CMML. The prognostic and diagnostic significance of these molecular lesions, in particular their value as biomarkers of response or resistance to specific therapies, while uncertain now is likely to be clarified as large systematic studies come to completion.
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PMID:Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: novel pathogenetic lesions. 2228 93

A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1(mut) patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2(mut) patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2(mut) patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2(mut) patients. U2AF35(mut) patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2(mut)/TET2(wt) (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.
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PMID:Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. 2234 20

Myelodysplastic/myeloproliferative uclassifiable (MDS/MPN-U) is a rare myeloid neoplasm characterized by myelodysplasia and myeloproliferation at the time of initial presentation, which is usually a diagnosis of exclusion. The molecular pathogenesis of MDS/MPN-U patients remains to be elucidated. Among five patients diagnosed with MDS/MPN-U, three patients harboured RUNX1 (AML1) mutations; one carried somatic mosaicism of RUNX1 mutation with JAK2(V617F) mutation and one had dual RUNX1 and FLT3-internal tandem duplication mutations with progression to acute myeloid leukaemia (AML). Germline mutation of TP53 was detected as a sole genetic lesion in one patient. JAK2(V617F) and somatic mosaicism of KRAS and TET2 mutations co-existed in one patient. Otherwise, no alterations were detected in PTPN11, NRAS, CBL and ASXL1 genes. ETV6-PDGFRB fusion transcript was not detected in all patients. Four patients recieved haematopoietic stem cell transplantation (HSCT); three patients relapsed and one achieved complete remission after three donor lymphocyte infusions. Our findings suggest that the mutational spectrum observed in childhood MDS/MPN-U is quite different from that seen in juvenile myelomonocytic leukaemia and, to some extent, resemble chronic myelomonocytic leukaemia. Moreover, two patients had constitutional alterations of genes frequently found in AML. Further investigations are required to define the roles of these genetic alterations in the pathogenesis of childhood MDS/MPN-U.
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PMID:De novo childhood myelodysplastic/myeloproliferative disease with unique molecular characteristics. 2257 58

TET2 haplo-insufficiency occurs through different molecular mechanisms and is promptly revealed by array comparative genomic hybridization, single nucleotide polymorphism (SNP) array, and next-generation sequencing (NGS). Fluorescence in situ hybridization (FISH) can effectively demonstrate TET2 deletions and is often used to validate molecular results. In the present study 41 MDS patients with and without 4q abnormalities were analyzed with a series of bacterial artificial chromosome (BAC) probes spanning the 4q22.3-q25 region. On conventional cytogenetic (CC) studies, a structural defect of the long arm of chromosome 4 (4q) was observed in seven patients. In three, one each with a t(1;4)(p21;q24), an ins(5;4)(q23;q24qter), and a t(4;17)(q31;p13) as the sole chromosomal abnormality, FISH with the RP11-356L5 and RP11-16G16 probes, which cover the TET2 locus, produced one signal only. Unexpectedly, this same result was achieved in 3 of the remaining 34 patients. Thus, a TET2 deletion was observed in a total of six patients (14.6%). TET2 deletion was not correlated with any particular clinical findings or outcome. These findings demonstrate that 1) FISH is an effective and economical method to reveal cryptic abnormalities of band 4q22-q24 resulting in TET2 deletions; 2) in these patients, TET2 deletion is the unifying genetic event; and 3) the different breakpoints within the 4q22-q25 region suggest that deletions are not mediated by repetitive sequences.
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PMID:Detection of TET2 abnormalities by fluorescence in situ hybridization in 41 patients with myelodysplastic syndrome. 2274 34

Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML.
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PMID:Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics. 2291 1

We investigated the prevalence of TET2 deletion by using a new FISH probe in a cohort of 362 Brazilian patients with myeloid neoplasms and their association with cytogenetic information (G-banding analysis). Normal karyotype was observed in 45.8 % of MDS (n = 44), 43.8 % of AML (n = 39) and 46.3 % of MPN (n = 82). Abnormalities of 4q24 (deletions, translocations or inversions) were associated with another chromosomal abnormality in four patients by G-banding analysis (2 MDS, 1 AML and 1 MPN). Interphase FISH analysis revealed deletion of TET2 in 21 patients (6 patients with abnormal karyotype and in 15 patients with normal karyotype). arrayCGH analysis revealed a cryptic deletion of the region 4q24 in all eight patients selected with myeloid malignancies (3 MDS, 1 AML and 4 MPN). Considering the significantly high cost of determining the mutational status of TET2 in patient samples by using conventional sequencing methods and sometimes the lack of regular use of SNP/aCGH array methodologies, FISH for the detection of TET2 abnormalities may become a potentially useful clinical tool. The search for alterations in TET2 gene may be important for the prediction of prognosis in normal/altered AML patients' karyotype or in the disease evolution of patients with MNP and MDS.
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PMID:FISH analysis for TET2 deletion in a cohort of 362 Brazilian myeloid malignancies: correlation with karyotype abnormalities. 2338 18

The clinical significance and mechanisms of TET2 are not well defined in myeloid malignancies. We detected TET2 mutations and assayed its catalyzing conversion product 5-hydroxymethylcytosine (5-hmC) in 61 Chinese patients with MDS. Ten patients were identified to have TET2 mutations (16.4%). 5-hmC levels in patients with MDS with TET2 mutations were significantly lower than in those without mutations, and CD34+ cells of patients with MDS exhibited a lower 5-hmC content than that of controls. TET2 expression and 5-hmC in patients with MDS with P15 methylation were both significantly lower than in those without P15 methylation. We did not observe a correlation between TET2 mutations and overall survival (OS) in MDS. Interestingly, we found that patients with MDS with higher 5-hmC levels or in lower risk groups of the Revised International Prognostic Scoring System (IPSS-R) had a longer overall survival, suggesting that 5-hmC levels may be a new molecular marker for prognostic assessment of MDS and that revised IPSS criteria are also applicable to the risk categories of Chinese patients with MDS.
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PMID:Decreased 5-hydroxymethylcytosine levels are associated with TET2 mutation and unfavorable overall survival in myelodysplastic syndromes. 2343 90


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