Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RUNX1 is a transcription factor that regulates critical processes in many aspects of hematopoiesis. RUNX1 is also integral in defining the definitive hematopoietic stem cell. In addition, many hematological diseases like myelodysplastic syndrome and myeloproliferative neoplasms have been associated with mutations in RUNX1. Located on chromosomal 21, the RUNX1 gene is involved in many forms of chromosomal translocations in leukemia. t(8;21) is one of the most common chromosomal translocations found in acute myeloid leukemia (AML), where it results in a fusion protein between RUNX1 and ETO. The RUNX1-ETO fusion protein is found in approximately 12% of all AML patients. In this review, we detail the structural features, functions, and models used to study both RUNX1 and RUNX1-ETO in hematopoiesis over the past two decades.
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PMID:RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. 2220 94

While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.
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PMID:Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. 2227 2

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

Cytotoxic chemotherapy for acute myeloid leukemia (AML) usually produces only temporary remissions, at the cost of significant toxicity and risk for death. One fundamental reason for treatment failure is that it is designed to activate apoptosis genes (eg, TP53) that may be unavailable because of mutation or deletion. Unlike deletion of apoptosis genes, genes that mediate cell cycle exit by differentiation are present in myelodysplastic syndrome (MDS) and AML cells but are epigenetically repressed: MDS/AML cells express high levels of key lineage-specifying transcription factors. Mutations in these transcription factors (eg, CEBPA) or their cofactors (eg., RUNX1) affect transactivation function and produce epigenetic repression of late-differentiation genes that antagonize MYC. Importantly, this aberrant epigenetic repression can be redressed clinically by depleting DNA methyltransferase 1 (DNMT1, a central component of the epigenetic network that mediates transcription repression) using the deoxycytidine analogue decitabine at non-cytotoxic concentrations. The DNMT1 depletion is sufficient to trigger upregulation of late-differentiation genes and irreversible cell cycle exit by p53-independent differentiation mechanisms. Fortuitously, the same treatment maintains or increases self-renewal of normal hematopoietic stem cells, which do not express high levels of lineage-specifying transcription factors. The biological rationale for this approach to therapy appears to apply to cancers other than MDS/AML also. Decitabine or 5-azacytidine dose and schedule can be rationalized to emphasize this mechanism of action, as an alternative or complement to conventional apoptosis-based oncotherapy.
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PMID:p53-Independent, normal stem cell sparing epigenetic differentiation therapy for myeloid and other malignancies. 2228 96

Mutations in genes of the splicing machinery have been described recently in myelodysplastic syndromes (MDS). In the present study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as described previously, SF3B1, in the context of other molecular markers, including mutations in ASXL1, RUNX1, NRAS, TP53, IDH1, IDH2, NPM1, and DNMT3A. Mutations in SRSF2, U2AF1, ZRSR2, and SF3B1 were found in 24 (12.4%), 14 (7.3%), 6 (3.1%), and 28 (14.5%) patients, respectively, corresponding to a total of 67 of 193 MDS patients (34.7%). SRSF2 mutations were associated with RUNX1 (P < .001) and IDH1 (P = .013) mutations, whereas U2AF1 mutations were associated with ASXL1 (P = .005) and DNMT3A (P = .004) mutations. In univariate analysis, mutated SRSF2 predicted shorter overall survival and more frequent acute myeloid leukemia progression compared with wild-type SRSF2, whereas mutated U2AF1, ZRSR2, and SF3B1 had no impact on patient outcome. In multivariate analysis, SRSF2 remained an independent poor risk marker for overall survival (hazard ratio = 2.3; 95% confidence interval, 1.28-4.13; P = .017) and acute myeloid leukemia progression (hazard ratio = 2.83; 95% confidence interval, 1.31-6.12; P = .008). These results show a negative prognostic impact of SRSF2 mutations in MDS. SRSF2 mutations may become useful for clinical risk stratification and treatment decisions in the future.
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PMID:Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. 2238 53

Leukemias including acute myeloid leukemia (AML), acute lymphocytic leukemia, and chronic myeloid leukemia as well as myelodysplastic syndrome (MDS), male non-Hodgkin lymphoma and MGUS are statistically significant radiation-associated hematopoietic neoplasms. Recently, MDS has been confirmed to increase among atomic bomb survivors. AML/RUNX1 is a critical transcription factor of differentiation and proliferation of hematopoietic stem cells. AML1 point mutations, especially N-terminal RUNT domain in-frame type, are frequently detected in radiaton-associated and therapy-related (rad-t-) MDS/AML. In addition, the point mutations, are frequently associated with additional mutations in receptor tyrosine kinase (RTK)-RAS pathway, including FLT3, N-RAS, SHP2 and NF1. The combination of AML1/RUNX1 mutation and RTK-RAS pathway mutation in hematopoietic stem cells is considered responsible for the oncogenesis of rad-t- MDS/AML.
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PMID:[Radiation associated leukemia and myelodysplastic syndrome]. 2251 21

The myelodysplastic syndromes (MDS) are heterogeneous and can evolve into acute myeloid leukaemia (AML). Rare familial cases are reported in which five disease genes have been identified to date (RUNX1, CEBPA, TERC, TERT and GATA2). Here we report the genetic categorization of 27 families with familial MDS/AML. All of these families were screened for RUNX1, CEBPA, TERC, TERT and GATA2 as well as TET2 and NPM1. Five of the 27 families had telomerase mutations; one had a RUNX1 mutation, while none were found to have TET2, CEBPA or NPM1 mutations. We identified four families with heterozygous GATA2 mutations, each associated with a different phenotype. While one of these mutations is novel, three have been previously reported: one has been described in dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and one is in a family that has been reported in a series with primary lymphoedema with a predisposition to AML (Emberger syndrome). In summary, genetic characterization was shown in 10 (four GATA2, three TERT, two TERC, one RUNX1) of these families; however 17 remain uncharacterized, highlighting marked genetic heterogeneity in familial MDS/AML and the scope for further functional pathways that could give rise to this group of disorders.
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PMID:Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. 2253 37

To determine whether the distinct and heterogeneous WHO category called "AML with myelodysplasia-related changes" (MRC-AML), presents specific molecular alterations we searched for mutations in genes known to be mutated in malignant myeloid diseases. In 48 MRC-AML patients analyzed, we found 17 mutations in ASXL1 (35%), eight in RUNX1 (17%), seven in TET2 (15%), 12 in IDH (n = 2) or IDH2 (n = 10) (25%), four in DNMT3A (8%), four in NPM1 (8%), and one in FLT3 (2%). Mutations were more frequent in the intermediate cytogenetic (IC) subgroup of 36 patients than in the unfavorable karyotype subgroup, with an average ratio mutations/patients of 1.36 [0-3] vs. 0.33 [0-2] (P < 0.001). Then, we compared these 36 patients with IC MRC-AML with a control panel of 37 no-MRC-AML patients, who had both IC and no dysplasia. IC MRC-AMLs were associated with higher incidence of ASXL1 mutations (47% vs. 0%, P < 0.001) and lower incidence of DNMT3A (6% vs. 38%, P = 0.001), NPM1 (11% vs. 62%, P < 0.001) and FLT3 (3% vs. 49%, P < 0.001) mutations. No difference was found in the incidence of IDH1/2 or TET2 mutations according to the presence of dysplasia. Complete remission rate after intensive treatment was lower in the MRC-AML group than in the no-MRC-AML group (48% vs. 78%, P = 0.023) and in wild type NPM1 patients (50% vs. 84%, P = 0.009). Our study showed that MRC-AML as defined in the WHO 2008 classification presents a specific mutation pattern characterized by a high frequency of ASXL1 mutations and a low rate of NPM1, FLT3, and DNMT3A mutations.
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PMID:Acute myeloid leukemia with myelodysplasia-related changes are characterized by a specific molecular pattern with high frequency of ASXL1 mutations. 2253 92

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

Myeloid malignant diseases comprise chronic (including myelodysplastic syndromes, myeloproliferative neoplasms and chronic myelomonocytic leukemia) and acute (acute myeloid leukemia) stages. They are clonal diseases arising in hematopoietic stem or progenitor cells. Mutations responsible for these diseases occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. CBL, FLT3, JAK2, RAS), transcription factors (e.g. CEBPA, ETV6, RUNX1), epigenetic regulators (e.g. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. SF3B1, SRSF2). Large-scale sequencing efforts will soon lead to the establishment of a comprehensive repertoire of these mutations, allowing for a better definition and classification of myeloid malignancies, the identification of new prognostic markers and therapeutic targets, and the development of novel therapies. Given the importance of epigenetic deregulation in myeloid diseases, the use of drugs targeting epigenetic regulators appears as a most promising therapeutic approach.
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PMID:Myeloid malignancies: mutations, models and management. 2282 77


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