Recent advances in understanding the molecular pathogenesis of myelodysplastic syndromes

Kulasekararaj, Austin; Mohamedali, Azim; Mufti, Ghulam J.

doi:10.1111/bjh.12435

Cited by 44 publications

(38 citation statements)

References 155 publications

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“…13 Unlike myeloproliferative neoplasms, in which a mutation in 1 of just 3 genes (JAK2, CALR, and MPL) that constitutively activate hematopoietic growth factor receptor signaling is present in .85% of cases, no single mutation class is dominant in MDS. Mutations in SF3B1 and TET2, each mutated in 20% to 25% of patients with MDS, are the most commonly described abnormalities to date.…”

Section: Introductionmentioning

confidence: 99%

Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes

Steensma

Bejar

Jaiswal

et al. 2015

Blood

1,615

1,296

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Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies.

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Section: Introductionmentioning

confidence: 99%

Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes

Steensma

Bejar

Jaiswal

et al. 2015

Blood

1,615

1,296

View full text Add to dashboard Cite

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“…The molecular basis of MDS has been recently elucidated by novel DNA sequencing technologies, and up to 80% of patients are known to have somatic genetic mutations [9][10][11]. Among the many genetic mutations, several genes such as TP53, RUNX1, ETV6, EZH2, ASXL1, U2AF1, and SRSF2 have been identified to have poor prognostic significance in MDS [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Wilms Tumor Gene 1 Expression as a Predictive Marker for Relapse and Survival after Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes

Yoon

Jeon

Yahng

et al. 2015

Biology of Blood and Marrow Transplantation

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Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is a major concern in myelodysplastic syndromes (MDS), but the role of Wilms tumor gene 1 (WT1) as a predictive marker for post-HSCT relapse remains to be validated. We measured WT1 transcript levels by real-time quantitative PCR from marrow samples of 82 MDS patients who underwent transplantation between 2009 and 2013. Pre-HSCT WT1 expression weakly correlated with marrow blast counts or International Prognostic Scoring System scores and failed to predict post-transplantation relapse. Regarding post-HSCT WT1, transcript levels of relapsed patients were significantly higher in comparison to those in remission. Further analysis using receiver operating characteristics curves showed that higher (>154 copies/10(4)ABL) 1-month post-HSCT WT1 resulted in a higher 3-year relapse rate (47.2% versus 6.9%, P < .001) with poorer disease-free survival (DFS) and overall survival at 3 years (41.7% versus 79.0% and 54.3% versus 82.1%, P = .003 and P = .033, respectively). Multivariate analysis after adjusting for pre-HSCT karyotype and chronic graft-versus-host disease (GVHD) also revealed that higher 1-month post-HSCT WT1 was an independent predictive marker for subsequent relapse (P = .002) and poorer DFS (P = .010). In the higher 1-month post-HSCT WT1 subgroup, patients with chronic GVHD showed lower relapse rate and favorable survival outcome. One month post-HSCT WT1 expression was a useful marker for minimal residual disease and relapse prediction in association with chronic GVHD in the context of HSCT for MDS.

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“…ultiple classes of genetic aberrations have been suggested as the cause of myelodysplastic syndromes (MDS) (1,2), including mutations in signal transduction, transcription factors, and epigenetic modifiers (3)(4)(5). Interestingly, recent genomewide sequencing studies revealed that mutations in genes encoding splicing factors are commonly associated with MDS and other hematological malignancies (6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing

Komeno

Huang

Qiu

et al. 2015

Molecular and Cellular Biology

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dMyelodysplastic syndromes (MDS) are a group of neoplasms characterized by ineffective myeloid hematopoiesis and various risks for leukemia. SRSF2, a member of the serine/arginine-rich (SR) family of splicing factors, is one of the mutation targets associated with poor survival in patients suffering from myelodysplastic syndromes. Here we report the biological function of SRSF2 in hematopoiesis by using conditional knockout mouse models. Ablation of SRSF2 in the hematopoietic lineage caused embryonic lethality, and Srsf2-deficient fetal liver cells showed significantly enhanced apoptosis and decreased levels of hematopoietic stem/progenitor cells. Induced ablation of SRSF2 in adult Mx1-Cre Srsf2 flox/flox mice upon poly(I):poly(C) injection demonstrated a significant decrease in lineage ؊ Sca ؉ c-Kit ؉ cells in bone marrow. To reveal the functional impact of myelodysplastic syndromes-associated mutations in SRSF2, we analyzed splicing responses on the MSD-L cell line and found that the missense mutation of proline 95 to histidine (P95H) and a P95-to-R102 in-frame 8-amino-acid deletion caused significant changes in alternative splicing. The affected genes were enriched in cancer development and apoptosis. These findings suggest that intact SRSF2 is essential for the functional integrity of the hematopoietic system and that its mutations likely contribute to development of myelodysplastic syndromes. Multiple classes of genetic aberrations have been suggested as the cause of myelodysplastic syndromes (MDS) (1, 2), including mutations in signal transduction, transcription factors, and epigenetic modifiers (3-5). Interestingly, recent genomewide sequencing studies revealed that mutations in genes encoding splicing factors are commonly associated with MDS and other hematological malignancies (6-15). One of these newly identified genes codes for the SRSF2 splicing factor (also known as SC35), and its mutations have been linked to poor survival among MDS patients (16,17). Most of the SRSF2 mutations occurred at proline 95, and the majority of these mutations changed this proline to histidine (P95H); less-frequent changes to leucine (P95L) and arginine (P95R) and in-frame deletion of 8 amino acids (aa) from P95 to R102 (⌬8aa) have also been reported previously (6,16,(18)(19)(20). However, the causal effect of these mutations on MDS development remains to be established. SRSF2 is one of the founding members of the serine/argininerich (SR) protein family of splicing factors (21). It is involved in both constitutive and regulated splicing. Homozygous germ line Srsf2 knockout (KO) mice are embryonically lethal (22), and conditional knockout (cKO) mice display various tissue-specific phenotypes (22-24). Importantly, Srsf2 downregulation in mouse embryonic fibroblasts results in G 2 /M cell cycle arrest and genomic instability (23). To date, systematic analysis of SRSF2 function in the blood system has not been reported except for its requirement in T cell development (24). Given the tight link of Srsf2 mutations to MDS, we ai...

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Recent advances in understanding the molecular pathogenesis of myelodysplastic syndromes

Cited by 44 publications

References 155 publications

Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes

Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes

Wilms Tumor Gene 1 Expression as a Predictive Marker for Relapse and Survival after Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes

SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing

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