Mammalian Polycomb-mediated repression of <i>Hox</i> genes requires the essential spliceosomal protein Sf3b1

Isono, Kyoichi; Mizutani-Koseki, Yoko; Komori, Toshihisa; Schmidt-Zachmann, Marion S.; Koseki, Haruhiko

doi:10.1101/gad.1284605

Cited by 108 publications

(118 citation statements)

References 27 publications

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“…Recent studies have suggested that spliceosomal proteins participate in cellular functions besides the original splicing function. Heterozygote mice of SF3b subunit 1 (another U2 small nuclear ribonucleoprotein component) knock-out exhibited various skeletal alterations along the anterior-posterior axis, with altered expression of Hox genes, and heterozygotes of SF3b subunit 2 display similar skeletal abnormality (40). Although these studies support our findings, the detailed mechanisms by which SF3b4 regulates the cell surface BMPRI-A remain to be elucidated.…”

Section: Discussioncontrasting

confidence: 42%

Splicing Factor 3b Subunit 4 Binds BMPR-IA and Inhibits Osteochondral Cell Differentiation

Watanabe

Shionyu

Kimura

et al. 2007

Journal of Biological Chemistry

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Section: Discussioncontrasting

confidence: 42%

Splicing Factor 3b Subunit 4 Binds BMPR-IA and Inhibits Osteochondral Cell Differentiation

Watanabe

Shionyu

Kimura

et al. 2007

Journal of Biological Chemistry

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“…GEP of MDS patients show HOX deregulation with high risk of transformation to AML 98 and that HOX upregulation is associated with poor prognosis AML, 99 although no study has yet correlated the deregulation of HOX genes with SF3B1 mutations. However, the study in mouse 97 shows that SF3B1 spliceosomal protein is required to repress HOX genes, so there may well be a link between these two genes in the context of human disease, as predicted by the mouse model.…”

Section: Spliceosomal Mutationsmentioning

confidence: 99%

“…93 Pro-apoptotic profile in young mice reduced levels of transcripts and protein exhibiting skeletal alterations with associated changes in ectopic homeobox transcription factor HOX gene expressions in the vertebrae of embryos, leading to the conclusion that SF3B1 mediates repression of HOX genes. 97 HOX gene abnormalities have been implicated in fusions giving rise to myeloid malignancies, as described below. GEP of MDS patients show HOX deregulation with high risk of transformation to AML 98 and that HOX upregulation is associated with poor prognosis AML, 99 although no study has yet correlated the deregulation of HOX genes with SF3B1 mutations.…”

Section: Spliceosomal Mutationsmentioning

confidence: 99%

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

2012

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Myelodysplastic syndromes represent particularly challenging hematologic malignancies that arise from a large spectrum of genetic events resulting in a disease characterized by a range of different presentations and outcomes. Despite efforts to classify and identify the key genetic events, little improvement has been made in therapies that will increase patient survival. Animal models represent powerful tools to model and study human diseases and are useful pre-clinical platforms. In addition to enforced expression of candidate oncogenes, gene inactivation has allowed the consequences of the genetic effects of human myelodysplastic syndrome to be studied in mice. This review aims to examine the animal models expressing myelodysplastic syndrome-associated genes that are currently available and to highlight the most appropriate model to phenocopy myelodysplastic syndrome disease and its risk of transformation to acute myelogenous leukemia. ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.069385 ABSTRACTMouse models myelodysplastic syndrome human candidate genes haematologica | 2013; 98 (1) 11 Figure 1. Mouse models to study malignant hematologic disease. Several strategies can be employed to create mouse models of disease. Candidate genes can be introduced into the germline under the control of appropriate promoters to drive expression in certain cell compartments. Knock-out strategies create gene deficient mice, whilst knock-in strategies use the endogenous promoters; but again these tend to be conditional systems requiring specific promoters to determine in which cell the genes are introduced. Transduction of bone marrow and reinfusion is a powerful tool. Xenograft models are theoretically the best if the techniques involved can be improved.

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“…Sf3b1-knockout mice exhibit a homeotic phenotype that has been suggested to be linked to Polycomb repressive complex activity. 18 In line with the above observations, it was recently demonstrated that hematopoietic stem/progenitor cells from patients with CLL were capable of generating clonal B cells with a CLL-like phenotype, thus implicating hematopoietic stem/progenitor cells www.nature.com/leu in the pathogenesis of CLL, a mature lymphoid malignancy. 19 Similarly, TET2 mutations are found in both myeloid and lymphoid malignancies and in both instances, the mutations may be present in myeloid progenitors, again suggesting a stem cell origin for some mature lymphoid malignancies.…”

Section: Sf3b1 Mutationsmentioning

confidence: 66%

“…35,36 Some of these effects might involve direct recruitment of splice factors by chromatin mark readers, as has been shown for MRG15 (also known as MORF4L1) binding to H3K36me3 and recruitment of the polypyrimidine tract-binding protein to the nascent mRNA. 37 The lack of SF3B1 may impair PRC1 function 18 and the SPT3-TAFII31-GCN5L acetylase complex may also interact with splice factors. 38 Mutations affecting 'splice genes' may therefore alter either upstream the efficiency of transcription or downstream the kinetics of mRNA export to the cytoplasm and/or lead to RNA degradation.…”

Section: Sf3b1 Mutationsmentioning

confidence: 99%

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

et al. 2012

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Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. Leukemia (2012Leukemia ( ) 26, 2027Leukemia ( -2031 doi:10.1038/leu.2012 Keywords: CLL; MDS; mutations; spliceosome INTRODUCTIONIn a series of recently published work, the coding sequences of the DNA obtained from mononuclear cells of the bone marrow of patients with myelodysplastic syndromes (MDSs) were compared with presumably germline DNA (T lymphocytes or buccal swab). [1][2][3] The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations. 1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA. Such mutations were mutually exclusive and were detected in 45-85% of patients with MDS; 1 the majority constituted missense mutations located in restricted regions of proteins.A similar analysis was conducted in chronic lymphocytic leukemia (CLL) where DNA from tumor cells (CD19 þ and CD5 þ lymphocytes) was compared with that of non-tumor cells (granulocytes or fibroblasts). [4][5][6][7] In addition to genes already known to be mutated in this disease, such as TP53 and ATM, 11 genes were found to be recurrently affected. 4,6 The pathway analyses predicted that these mutations affected DNA damage repair and cell cycle, the Wnt, NOTCH1 and inflammatory/TLR signaling pathways, and, as was the case in MDS, control of splicing mechanisms. 4 The common novel observation, from the above-mentioned studies, in both MDS and CLL, was the identification of mutations in genes whose products are involved in the control of RNA splicing. 8 The involvement of oncogenes in RNA processing h...

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Mammalian Polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1

Cited by 108 publications

References 27 publications

Splicing Factor 3b Subunit 4 Binds BMPR-IA and Inhibits Osteochondral Cell Differentiation

Splicing Factor 3b Subunit 4 Binds BMPR-IA and Inhibits Osteochondral Cell Differentiation

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

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