Physiological Srsf2 P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice

Splicing factor mutations are characteristic of myelodysplastic syndromes (MDS) and related myeloid neoplasms and implicated in their pathogenesis, but their roles in the development of MDS have not been fully elucidated. In the present study, we investigated the consequence of mutant Srsf2 expression using newly generated Vav1-Cre–mediated conditional knockin mice. Mice carrying a heterozygous Srsf2 P95H mutation showed significantly reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and differentiation defects both in the steady-state condition and transplantation settings. Srsf2-mutated hematopoietic stem cells (HSCs) showed impaired long-term reconstitution compared with control mice in competitive repopulation assays. Although the Srsf2 mutant mice did not develop MDS under the steady-state condition, when their stem cells were transplanted into lethally irradiated mice, the recipients developed anemia, leukopenia, and erythroid dysplasia, which suggests the role of replicative stress in the development of an MDS-like phenotype in Srsf2-mutated mice. RNA sequencing of the Srsf2-mutated HSPCs revealed a number of abnormal splicing events and differentially expressed genes, including several potential targets implicated in the pathogenesis of hematopoietic malignancies, such as Csf3r, Fyn, Gnas, Nsd1, Hnrnpa2b1, and Trp53bp1. Among the mutant Srsf2-associated splicing events, most commonly observed were the enhanced inclusion and/or exclusion of casse...
Source: Blood - Category: Hematology Authors: Tags: Hematopoiesis and Stem Cells, Myeloid Neoplasia Source Type: research

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Authors: Sachiyo O, Masahiro T, Tsutomu T, Makoto I, Yutaka H, Nobumasa M, Takamichi K, Nozomi O, Shinpei M, Kazuhiro T, Yusuke K, Masanori O, Yusuke K, Yasuhisa H, Kazuo H, Yasumasa N Abstract Fanconi anemia (FA) is a disorder of chromosomal fragility characterized by progression to aplastic anemia, myelodysplastic syndrome, and leukemia. FA patients are also predisposed to solid cancers. A case of FA in an adult patient who developed tongue and superficial esophageal cancers following hematopoietic stem cell transplantation is reported. This case was considered significant because it is the first reported case of...
Source: Internal Medicine - Category: Internal Medicine Tags: Intern Med Source Type: research
CONCLUSION: Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710-1719. PMID: 30334483 [PubMed - in process]
Source: Orvosi Hetilap - Category: General Medicine Authors: Tags: Orv Hetil Source Type: research
CONCLUSIONS: We found no evidence for a difference between participants receiving ATRA in addition to chemotherapy or chemotherapy only for the outcome OS. Regarding DFS, CRR and on-study mortality, there is probably no evidence for a difference between treatment groups. Currently, it seems the risk of adverse events are comparable to chemotherapy only.As quality of life has not been evaluated in any of the included trials, further research is needed to clarify the effect of ATRA on quality of life. PMID: 30080246 [PubMed - as supplied by publisher]
Source: Cochrane Database of Systematic Reviews - Category: General Medicine Authors: Tags: Cochrane Database Syst Rev Source Type: research
Publication date: Available online 30 July 2018Source: Clinical Lymphoma Myeloma and LeukemiaAuthor(s): Chetasi Talati, David Sallman, Alan F. ListAbstractMyelodysplastic syndrome (MDS) with deletion 5q (del(5q)) is a distinct clinical and pathological disease subset that is exquisitely sensitive to lenalidomide for the treatment of red blood cell transfusion-dependent anemia. Lenalidomide resistance, including primary resistance occurs via clonal evolution which is frequently attributable to the presence of somatic mutations in in the DNA-binding domain of the TP53 gene. Treatment options after development of resistance t...
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Monosomy 7 (–7) and del(7q) are high-risk cytogenetic abnormalities common in myeloid malignancies. We previously reported that CUX1, a homeodomain-containing transcription factor encoded on 7q22, is frequently inactivated in myeloid neoplasms, and CUX1 myeloid tumor suppressor activity is conserved from humans to Drosophila. CUX1-inactivating mutations are recurrent in clonal hematopoiesis of indeterminate potential as well as myeloid malignancies, in which they independently carry a poor prognosis. To determine the role for CUX1 in hematopoiesis, we generated 2 short hairpin RNA-based mouse models with ~54% (Cux1mi...
Source: Blood - Category: Hematology Authors: Tags: Hematopoiesis and Stem Cells, Myeloid Neoplasia Source Type: research
Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders with an annual incidence of 1 to 4 cases per million, accounting for less than 5% of childhood hematologic malignancies. MDSs in children often occur in the context of inherited bone marrow failure syndromes, which represent a peculiarity of myelodysplasia diagnosed in pediatric patients. Moreover, germ line syndromes predisposing individuals to develop MDS or acute myeloid leukemia have recently been identified, such as those caused by mutations in GATA2, ETV6, SRP72, and SAMD9/SAMD9-L. Refractory cytopenia of childhood (RCC) is the m...
Source: Blood - Category: Hematology Authors: Tags: Pediatric Hematology, Transplantation, How I Treat, Free Research Articles, Myeloid Neoplasia Source Type: research
Background: Studies of bone marrow cell clonal alterations in patients with Fanconi anemia (FA), a cancer-prone inherited bone marrow failure (BMF) syndrome, have focused on their role in progression from BMF to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The role of such alterations on patient outcomes after hematopoietic cell transplantation (HCT) is unknown.
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
Authors: Alter BP Abstract Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications...
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research
Abstract Disease overviewThe myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy. DiagnosisDiagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is usually complementary and may help refine diagnosis. Ri...
Source: American Journal of Hematology - Category: Hematology Authors: Tags: ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES Source Type: research
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with ...
Source: Blood - Category: Hematology Authors: Tags: Hematopoiesis and Stem Cells, Transplantation, Review Articles, Clinical Trials and Observations Source Type: research
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