Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia
SF3B1 is a core component of the mRNA splicing machinery and frequently mutated in myeloid neoplasms with myelodysplasia, particularly in those characterized by the presence of increased ring sideroblasts. Deregulated RNA splicing is implicated in the pathogenesis of SF3B1 -mutated neoplasms, but th...
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| Veröffentlicht in: | Leukemia 2014-09, Vol.28 (9), p.1844-1850 |
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| creator | Matsunawa, M Yamamoto, R Sanada, M Sato-Otsubo, A Shiozawa, Y Yoshida, K Otsu, M Shiraishi, Y Miyano, S Isono, K Koseki, H Nakauchi, H Ogawa, S |
| description | SF3B1 is a core component of the mRNA splicing machinery and frequently mutated in myeloid neoplasms with myelodysplasia, particularly in those characterized by the presence of increased ring sideroblasts. Deregulated RNA splicing is implicated in the pathogenesis of
SF3B1
-mutated neoplasms, but the exact mechanism by which the
SF3B1
mutation is associated with myelodysplasia and the increased ring sideroblasts formation is still unknown. We investigated the functional role of SF3B1 in normal hematopoiesis utilizing
Sf3b1
heterozygous-deficient mice.
Sf3b1
+/−
mice had a significantly reduced number of hematopoietic stem cells (CD34
−
cKit
+
ScaI
+
Lin
−
cells or CD34
−
KSL cells) compared with
Sf3b1
+/+
mice, but hematopoiesis was grossly normal in
Sf3b1
+/−
mice. When transplanted competitively with
Sf3b1
+/+
bone marrow cells,
Sf3b1
+/−
stem cells showed compromised reconstitution capacity in lethally irradiated mice. There was no increase in the number of ring sideroblasts or evidence of myeloid dysplasia in
Sf3b1
+/−
mice. These data suggest that
SF3B1
plays an important role in the regulation of hematopoietic stem cells, whereas
SF3B1
haploinsufficiency itself is not associated with the myelodysplastic syndrome phenotype with ring sideroblasts. |
| doi_str_mv | 10.1038/leu.2014.73 |
| format | Article |
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SF3B1
-mutated neoplasms, but the exact mechanism by which the
SF3B1
mutation is associated with myelodysplasia and the increased ring sideroblasts formation is still unknown. We investigated the functional role of SF3B1 in normal hematopoiesis utilizing
Sf3b1
heterozygous-deficient mice.
Sf3b1
+/−
mice had a significantly reduced number of hematopoietic stem cells (CD34
−
cKit
+
ScaI
+
Lin
−
cells or CD34
−
KSL cells) compared with
Sf3b1
+/+
mice, but hematopoiesis was grossly normal in
Sf3b1
+/−
mice. When transplanted competitively with
Sf3b1
+/+
bone marrow cells,
Sf3b1
+/−
stem cells showed compromised reconstitution capacity in lethally irradiated mice. There was no increase in the number of ring sideroblasts or evidence of myeloid dysplasia in
Sf3b1
+/−
mice. These data suggest that
SF3B1
plays an important role in the regulation of hematopoietic stem cells, whereas
SF3B1
haploinsufficiency itself is not associated with the myelodysplastic syndrome phenotype with ring sideroblasts.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2014.73</identifier><identifier>PMID: 24535406</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/136/232/1473/1542 ; 692/420/2489/68 ; 692/699/67/1990/1673 ; Animals ; Biology ; Bone marrow ; Bone marrow transplantation ; Cancer Research ; CD34 antigen ; Critical Care Medicine ; Cytokines ; Deregulation ; Development and progression ; Gene Expression Regulation ; Genetic aspects ; Genetic research ; Genomes ; Genotype & phenotype ; Haploinsufficiency ; Hematology ; Hematopoiesis ; Hematopoietic stem cells ; Hematopoietic Stem Cells - physiology ; Intensive ; Internal Medicine ; Leukemia ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred C57BL ; mRNA ; Mutation ; Myelodysplastic syndrome ; Myelodysplastic syndromes ; Myelodysplastic Syndromes - genetics ; Neoplasms ; Oncology ; original-article ; Pathogenesis ; Phenotypes ; Phosphoproteins - genetics ; Ribonucleoprotein, U2 Small Nuclear - genetics ; RNA splicing ; RNA Splicing Factors ; Sideroblasts ; Software ; Stem cell transplantation ; Stem cells ; Tumors</subject><ispartof>Leukemia, 2014-09, Vol.28 (9), p.1844-1850</ispartof><rights>Macmillan Publishers Limited 2014</rights><rights>COPYRIGHT 2014 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 2014</rights><rights>Macmillan Publishers Limited 2014.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c583t-cc9577de7a1af25307a7ffe3e1ba0e8ca2e09ebce6bd1e2289aa2c700b3c0a5b3</citedby><cites>FETCH-LOGICAL-c583t-cc9577de7a1af25307a7ffe3e1ba0e8ca2e09ebce6bd1e2289aa2c700b3c0a5b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2014.73$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2014.73$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24535406$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matsunawa, M</creatorcontrib><creatorcontrib>Yamamoto, R</creatorcontrib><creatorcontrib>Sanada, M</creatorcontrib><creatorcontrib>Sato-Otsubo, A</creatorcontrib><creatorcontrib>Shiozawa, Y</creatorcontrib><creatorcontrib>Yoshida, K</creatorcontrib><creatorcontrib>Otsu, M</creatorcontrib><creatorcontrib>Shiraishi, Y</creatorcontrib><creatorcontrib>Miyano, S</creatorcontrib><creatorcontrib>Isono, K</creatorcontrib><creatorcontrib>Koseki, H</creatorcontrib><creatorcontrib>Nakauchi, H</creatorcontrib><creatorcontrib>Ogawa, S</creatorcontrib><title>Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>SF3B1 is a core component of the mRNA splicing machinery and frequently mutated in myeloid neoplasms with myelodysplasia, particularly in those characterized by the presence of increased ring sideroblasts. Deregulated RNA splicing is implicated in the pathogenesis of
SF3B1
-mutated neoplasms, but the exact mechanism by which the
SF3B1
mutation is associated with myelodysplasia and the increased ring sideroblasts formation is still unknown. We investigated the functional role of SF3B1 in normal hematopoiesis utilizing
Sf3b1
heterozygous-deficient mice.
Sf3b1
+/−
mice had a significantly reduced number of hematopoietic stem cells (CD34
−
cKit
+
ScaI
+
Lin
−
cells or CD34
−
KSL cells) compared with
Sf3b1
+/+
mice, but hematopoiesis was grossly normal in
Sf3b1
+/−
mice. When transplanted competitively with
Sf3b1
+/+
bone marrow cells,
Sf3b1
+/−
stem cells showed compromised reconstitution capacity in lethally irradiated mice. There was no increase in the number of ring sideroblasts or evidence of myeloid dysplasia in
Sf3b1
+/−
mice. These data suggest that
SF3B1
plays an important role in the regulation of hematopoietic stem cells, whereas
SF3B1
haploinsufficiency itself is not associated with the myelodysplastic syndrome phenotype with ring sideroblasts.</description><subject>631/136/232/1473/1542</subject><subject>692/420/2489/68</subject><subject>692/699/67/1990/1673</subject><subject>Animals</subject><subject>Biology</subject><subject>Bone marrow</subject><subject>Bone marrow transplantation</subject><subject>Cancer Research</subject><subject>CD34 antigen</subject><subject>Critical Care Medicine</subject><subject>Cytokines</subject><subject>Deregulation</subject><subject>Development and progression</subject><subject>Gene Expression Regulation</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Genomes</subject><subject>Genotype & phenotype</subject><subject>Haploinsufficiency</subject><subject>Hematology</subject><subject>Hematopoiesis</subject><subject>Hematopoietic stem cells</subject><subject>Hematopoietic Stem Cells - physiology</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Leukemia</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>mRNA</subject><subject>Mutation</subject><subject>Myelodysplastic syndrome</subject><subject>Myelodysplastic syndromes</subject><subject>Myelodysplastic Syndromes - genetics</subject><subject>Neoplasms</subject><subject>Oncology</subject><subject>original-article</subject><subject>Pathogenesis</subject><subject>Phenotypes</subject><subject>Phosphoproteins - genetics</subject><subject>Ribonucleoprotein, U2 Small Nuclear - genetics</subject><subject>RNA splicing</subject><subject>RNA Splicing Factors</subject><subject>Sideroblasts</subject><subject>Software</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Tumors</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqFks9rFTEQx4Mo9lk9eZeAUATdZ35sfuyxFLVCwYN6lJDNTtqUbPLc7B7ef2_WV7WVouQQyHxm5juTL0LPKdlSwvXbCMuWEdpuFX-ANrRVshFC0IdoQ7RWjexYe4SelHJNyBqUj9ERawUXLZEb9O3c7mIOqSzeBxcguT3OHn_2vKc4gh0KnjN2edxNeQwFBlxmGLGDGLFfkptDTrhfZpzyvJLjHmIe9mUXbQn2KXrkbSzw7OY-Rl_fv_tydt5cfPrw8ez0onFC87lxrhNKDaAstZ4JTpRV3gMH2lsC2lkGpIPegewHCozpzlrmFCE9d8SKnh-jV4e6VeX3BcpsqtZVo02Ql2KoZExSKhT_PyokIV2r266iL_9Cr_MypTqIYbKtxXQryL8oKkRHqKZS_aEubQQTks_zZN3a2pxyzaRQnVw7bu-h6hlgDC4n8KG-30k4uZVwBTbOVyXHZf2Wchd8fQDdlEuZwJvdFEY77Q0lZrWRqTYyq43MzyW9uJlp6UcYfrO_fFOBNweg1FC6hOnW0PfU-wHhbs73</recordid><startdate>20140901</startdate><enddate>20140901</enddate><creator>Matsunawa, M</creator><creator>Yamamoto, R</creator><creator>Sanada, M</creator><creator>Sato-Otsubo, A</creator><creator>Shiozawa, Y</creator><creator>Yoshida, K</creator><creator>Otsu, M</creator><creator>Shiraishi, Y</creator><creator>Miyano, S</creator><creator>Isono, K</creator><creator>Koseki, H</creator><creator>Nakauchi, H</creator><creator>Ogawa, S</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20140901</creationdate><title>Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia</title><author>Matsunawa, M ; Yamamoto, R ; Sanada, M ; Sato-Otsubo, A ; Shiozawa, Y ; Yoshida, K ; Otsu, M ; Shiraishi, Y ; Miyano, S ; Isono, K ; Koseki, H ; Nakauchi, H ; Ogawa, S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c583t-cc9577de7a1af25307a7ffe3e1ba0e8ca2e09ebce6bd1e2289aa2c700b3c0a5b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>631/136/232/1473/1542</topic><topic>692/420/2489/68</topic><topic>692/699/67/1990/1673</topic><topic>Animals</topic><topic>Biology</topic><topic>Bone marrow</topic><topic>Bone marrow transplantation</topic><topic>Cancer Research</topic><topic>CD34 antigen</topic><topic>Critical Care Medicine</topic><topic>Cytokines</topic><topic>Deregulation</topic><topic>Development and progression</topic><topic>Gene Expression Regulation</topic><topic>Genetic aspects</topic><topic>Genetic research</topic><topic>Genomes</topic><topic>Genotype & phenotype</topic><topic>Haploinsufficiency</topic><topic>Hematology</topic><topic>Hematopoiesis</topic><topic>Hematopoietic stem cells</topic><topic>Hematopoietic Stem Cells - physiology</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Leukemia</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>mRNA</topic><topic>Mutation</topic><topic>Myelodysplastic syndrome</topic><topic>Myelodysplastic syndromes</topic><topic>Myelodysplastic Syndromes - genetics</topic><topic>Neoplasms</topic><topic>Oncology</topic><topic>original-article</topic><topic>Pathogenesis</topic><topic>Phenotypes</topic><topic>Phosphoproteins - genetics</topic><topic>Ribonucleoprotein, U2 Small Nuclear - genetics</topic><topic>RNA splicing</topic><topic>RNA Splicing Factors</topic><topic>Sideroblasts</topic><topic>Software</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Matsunawa, M</creatorcontrib><creatorcontrib>Yamamoto, R</creatorcontrib><creatorcontrib>Sanada, M</creatorcontrib><creatorcontrib>Sato-Otsubo, A</creatorcontrib><creatorcontrib>Shiozawa, Y</creatorcontrib><creatorcontrib>Yoshida, K</creatorcontrib><creatorcontrib>Otsu, M</creatorcontrib><creatorcontrib>Shiraishi, Y</creatorcontrib><creatorcontrib>Miyano, S</creatorcontrib><creatorcontrib>Isono, K</creatorcontrib><creatorcontrib>Koseki, H</creatorcontrib><creatorcontrib>Nakauchi, H</creatorcontrib><creatorcontrib>Ogawa, S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matsunawa, M</au><au>Yamamoto, R</au><au>Sanada, M</au><au>Sato-Otsubo, A</au><au>Shiozawa, Y</au><au>Yoshida, K</au><au>Otsu, M</au><au>Shiraishi, Y</au><au>Miyano, S</au><au>Isono, K</au><au>Koseki, H</au><au>Nakauchi, H</au><au>Ogawa, S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2014-09-01</date><risdate>2014</risdate><volume>28</volume><issue>9</issue><spage>1844</spage><epage>1850</epage><pages>1844-1850</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>SF3B1 is a core component of the mRNA splicing machinery and frequently mutated in myeloid neoplasms with myelodysplasia, particularly in those characterized by the presence of increased ring sideroblasts. Deregulated RNA splicing is implicated in the pathogenesis of
SF3B1
-mutated neoplasms, but the exact mechanism by which the
SF3B1
mutation is associated with myelodysplasia and the increased ring sideroblasts formation is still unknown. We investigated the functional role of SF3B1 in normal hematopoiesis utilizing
Sf3b1
heterozygous-deficient mice.
Sf3b1
+/−
mice had a significantly reduced number of hematopoietic stem cells (CD34
−
cKit
+
ScaI
+
Lin
−
cells or CD34
−
KSL cells) compared with
Sf3b1
+/+
mice, but hematopoiesis was grossly normal in
Sf3b1
+/−
mice. When transplanted competitively with
Sf3b1
+/+
bone marrow cells,
Sf3b1
+/−
stem cells showed compromised reconstitution capacity in lethally irradiated mice. There was no increase in the number of ring sideroblasts or evidence of myeloid dysplasia in
Sf3b1
+/−
mice. These data suggest that
SF3B1
plays an important role in the regulation of hematopoietic stem cells, whereas
SF3B1
haploinsufficiency itself is not associated with the myelodysplastic syndrome phenotype with ring sideroblasts.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24535406</pmid><doi>10.1038/leu.2014.73</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2014-09, Vol.28 (9), p.1844-1850 |
| issn | 0887-6924 1476-5551 |
| language | eng |
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| source | MEDLINE; Nature; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SpringerNature Journals |
| subjects | 631/136/232/1473/1542 692/420/2489/68 692/699/67/1990/1673 Animals Biology Bone marrow Bone marrow transplantation Cancer Research CD34 antigen Critical Care Medicine Cytokines Deregulation Development and progression Gene Expression Regulation Genetic aspects Genetic research Genomes Genotype & phenotype Haploinsufficiency Hematology Hematopoiesis Hematopoietic stem cells Hematopoietic Stem Cells - physiology Intensive Internal Medicine Leukemia Medicine Medicine & Public Health Mice Mice, Inbred C57BL mRNA Mutation Myelodysplastic syndrome Myelodysplastic syndromes Myelodysplastic Syndromes - genetics Neoplasms Oncology original-article Pathogenesis Phenotypes Phosphoproteins - genetics Ribonucleoprotein, U2 Small Nuclear - genetics RNA splicing RNA Splicing Factors Sideroblasts Software Stem cell transplantation Stem cells Tumors |
| title | Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia |
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