Mutations of ASXL1 and TET2 in aplastic anemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Huang J
PROVIDER: S-EPMC4420224 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
Mutations of ASXL1 and TET2 in aplastic anemia.
Huang Jinbo J Ge Meili M Lu Shihong S Shi Jun J Li Xingxin X Zhang Jizhou J Wang Min M Yu Wei W Shao Yingqi Y Huang Zhendong Z Zhang Jing J Nie Neng N Zheng Yizhou Y
Haematologica 20150116 5
Similar Datasets
Project description:Mutations involving epigenetic regulators (TET2~60% and ASXL1~40%) and splicing components (SRSF2~50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had >3 mutations. In a univariate analysis, the presence of ASXL1 mutations (P=0.02) and the absence of TET2 mutations (P=0.03), adversely impacted survival; while the number of concurrent mutations had no impact (P=0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (P=0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt (n=56), ASXL1mut/TET2wt (n=31), ASXL1mut/TET2mut (n=50) and ASXL1wt/TET2mut (n=38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P=0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) (P=0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations.
| S-EPMC4742630 | biostudies-other
Project description:BACKGROUND:In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. METHODS:We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. RESULTS:Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. CONCLUSIONS:Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).
| S-EPMC7478337 | biostudies-literature
Project description:Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural killer cells. Inherited perforin mutations account for 20% to 40% of familial hemophagocytic lymphohistiocytosis, a fatal disease of early childhood characterized by the absence of functional perforin. Aplastic anemia, the paradigm of immune-mediated bone marrow failure syndromes, is characterized by hematopoietic stem cell destruction by activated T cells and Th1 cytokines. We examined whether mutations in the perforin gene occurred in acquired aplastic anemia. Three nonsynonymous PRF1 mutations among 5 unrelated patients were observed. Four of 5 patients with the mutations showed some hemophagocytosis in the bone marrow at diagnosis. Perforin protein levels in these patients were very low or absent, and perforin granules were completely absent. Natural killer (NK) cell cytotoxicity from these patients was significantly decreased. Our data suggest that PRF1 genetic alterations help explain the aberrant proliferation and activation of cytotoxic T cells and may represent genetic risk factors for bone marrow failure.
| S-EPMC1890825 | biostudies-literature
Project description:Shwachman-Diamond syndrome (SDS; OMIM 260400), an inherited bone marrow failure syndrome, is caused by mutations in both alleles of the SBDS gene, which encodes a protein of unknown function. Here we report heterozygosity for the 258 + 2 T>C SBDS gene mutation previously identified in SDS patients in 4 of 91 patients with apparently acquired aplastic anemia (AA) but not in 276 ethnically matched controls (Fisher exact test, P < .004). Affected patients were young and had a poor outcome; they had reduced SBDS expression but no evidence of the pancreatic exocrine failure or skeletal abnormalities typical of SDS. Length of telomeres in granulocytes of SBDS heterozygous patients was short for their age, and in SDS patients with both SBDS alleles affected further analyzed, granulocytes' telomeres were even shorter, correlating in length with SBDS expression. Higher heterogeneity in telomere length also was observed in SDS patients. Telomerase activity of SBDS-deficient patients' lymphocytes was comparable with controls, and no physical interaction between SBDS protein and telomerase complex components (TERT or TERC) was established. We propose that heterozygosity for the 258 + 2 T>C SBDS mutation predisposes to AA by accelerating telomere shortening of leukocytes via a telomerase-independent mechanism.
| S-EPMC1939897 | biostudies-literature
Project description:Reduced osteogenic capacity of bone marrow mesenchymal stem cells (BMSCs) has been causally linked to the development of aplastic anemia. In this work, we aimed to identify novel microRNAs (miRNAs) that participate in the regulation of differentiation of BMSCs from patients with aplastic anemia. We show that miR-144-3p is significantly upregulated in BMSCs from patients with aplastic anemia relative to control equivalents. Depletion of miR-144-3p significantly enhances osteogenic differentiation of BMSCs from patients with aplastic anemia after culturing in osteogenesis-inducing medium. Conversely, overexpression of miR-144-3p blocks osteogenic differentiation of BMSCs. Mechanistically, miR-144-3p negatively regulates the expression of ten-eleven translocation 2 (TET2) in BMSCs. Reduced TET2 expression is associated with a significant decrease in global 5-hydroxymethyl-cytosine (5hmC) levels and osteogenic gene expression. Knockdown of miR-144-3p elevates the expression of TET2 and total 5hmC levels in BMSCs. Silencing of TET2 inhibits the osteogenic differentiation of BMSCs. Overexpression of TET2 reverses miR-144-3p-mediated inhibition of osteogenesis. In addition, there is a significant negative correlation between the expression of miR-144-3p and TET2 in BMSCs from patients with aplastic anemia. Overall, miR-144-3p impairs the osteogenic capacity of BMSCs from patients with aplastic anemia through repression of TET2. Therefore, the targeting of miR-144-3p may be a therapeutic strategy against aplastic anemia.
| S-EPMC6965517 | biostudies-literature
Project description:We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.
| S-EPMC3419680 | biostudies-literature
Project description:The development of thrombotic events is common among patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We studied the influence of pathogenic mutations frequently associated with myeloid malignancies on thrombotic events using next-generation sequencing (NGS) in an initial cohort of 68 patients with myeloproliferative neoplasms (MPN). As expected, the presence of mutations in DNMT3A, TET2, and ASXL1 (DTA genes) was positively associated with age for the whole cohort (p = 0.025, OR: 1.047, 95% CI: 1.006-1.090). Also, while not related with events in the whole cohort, DTA mutations were strongly associated with the development of vascular events in PV patients (p = 0.028). To confirm the possible association between the presence of DTA mutation and thrombotic events, we performed a case-control study on 55 age-matched patients with PV (including 12 PV patients from the initial cohort, 25 with event vs. 30 no event). In the age-matched case-control PV cohort, the presence of ≥1 DTA mutation significantly increased the risk of a thrombotic event (OR: 6.333, p = 0.0024). Specifically, mutations in TET2 were associated with thrombotic events in the PV case-control cohort (OR: 3.56, 95% CI: 1.15-11.83, p = 0.031). Our results suggest that pathogenic DTA mutations, and particularly TET2 mutations, may be an independent risk factor for thrombosis in patients with PV. However, the predictive value of TET2 and DTA mutations in ET and PMF was inconclusive and should be determined in a larger cohort.
| S-EPMC7226609 | biostudies-literature
Project description:Aplastic anemia (AA) is a potentially fatal bone marrow failure syndrome characterized by a paucity of hematopoietic stem cells and progenitor cells with varying degrees of cytopenia and fatty infiltration of the bone marrow space. Recent advances in genomics have uncovered a link between somatic mutations and myeloid cancer in AA patients. At present, the impact of these mutations on AA patients remains uncertain. We retrospectively investigated 279 AA patients and 174 patients with myelodysplastic syndromes (MDS) and performed targeted sequencing of 22 genes on their bone marrow cells using next-generation sequencing (NGS). Associations of somatic mutations with prognostic relevance and response to treatment were analyzed. Of 279 AA patients, 25 (9.0%) patients had somatic mutations, and 20 (7.2%) patients had one mutation. The most frequently mutated genes were ASXL1(3.2% of the patients), DNMT3A (1.8%) and TET2 (1.8%). In the MDS group, somatic mutations were detected in 120 of 174 (69.0%) patients, and 81 patients (46.6%) had more than one mutation. The most frequently mutated genes were U2AF1 (24.7% of the patients), ASXL1 (18.4%) and TP53 (13.2%). Compared with MDS patients, AA patients had a significantly lower frequency of somatic mutations and mostly one mutation. Similarly, the median variant allele frequency was lower in AA patients than in MDS patients (6.9% vs. 28.4%). The overall response of 3 and 6 months in the somatic mutation (SM) group was 37.5% and 66.7%, respectively. Moreover, there was no significant difference compared with the no somatic mutation (N-SM) group. During the 2-years follow-up period, four (20%) deaths occurred in the SM group and 40 (18.1%) in the N-SM group, with no significant difference in overall survival and event-free survival between the two groups. Our data indicated that myeloid tumor-associated somatic mutations in AA patients were detected in only a minority of patients by NGS. AA and MDS patients had different gene mutation patterns. The somatic mutations in patients with AA were characterized by lower mutation frequency, mostly one mutation, and lower median allelic burden of mutations than MDS. Somatic mutations were a common finding in the elderly, and the frequency of mutations increases with age. The platelet count affected the treatment response at 3 months, and ferritin level affected the outcome at 6 months, while somatic mutations were not associated with treatment response or long-term survival. However, our cohort of patients with the mutation was small; this result needs to be further confirmed with large patient sample.
| S-EPMC10725342 | biostudies-literature
Project description:The prevalence and functional impact of somatic mutations in nonleukemic T cells is not well characterized, although clonal T-cell expansions are common. In immune-mediated aplastic anemia (AA), cytotoxic T-cell expansions are shown to participate in disease pathogenesis. We investigated the mutation profiles of T cells in AA by a custom panel of 2533 genes. We sequenced CD4+ and CD8+ T cells of 24 AA patients and compared the results to 20 healthy controls and whole-exome sequencing of 37 patients with AA. Somatic variants were common both in patients and healthy controls but enriched to AA patients' CD8+ T cells, which accumulated most mutations on JAK-STAT and MAPK pathways. Mutation burden was associated with CD8+ T-cell clonality, assessed by T-cell receptor beta sequencing. To understand the effect of mutations, we performed single-cell sequencing of AA patients carrying STAT3 or other mutations in CD8+ T cells. STAT3 mutated clone was cytotoxic, clearly distinguishable from other CD8+ T cells, and attenuated by successful immunosuppressive treatment. Our results suggest that somatic mutations in T cells are common, associate with clonality, and can alter T-cell phenotype, warranting further investigation of their role in the pathogenesis of AA.
| S-EPMC8102188 | biostudies-literature
Project description: Not available
| S-EPMC8925687 | biostudies-literature