The impact of SF3B1 mutations in CLL on the DNA-damage response
Mutations or deletions in TP53 or ATM are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associat...
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| creator | te Raa, G D Derks, I A M Navrkalova, V Skowronska, A Moerland, P D van Laar, J Oldreive, C Monsuur, H Trbusek, M Malcikova, J Lodén, M Geisler, C H Hüllein, J Jethwa, A Zenz, T Pospisilova, S Stankovic, T van Oers, M H J Kater, A P Eldering, E |
| description | Mutations or deletions in
TP53
or
ATM
are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with
ATM
aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (
n
=110) containing
ATM
,
SF3B1
and
TP53
gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly,
SF3B1
mutated samples without concurrent
ATM
and
TP53
aberrations (sole
SF3B1
) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast,
NOTCH1
or
K/N-RAS
mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole
SF3B1
mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with
SF3B1
mutations. |
| doi_str_mv | 10.1038/leu.2014.318 |
| format | Article |
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TP53
or
ATM
are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with
ATM
aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (
n
=110) containing
ATM
,
SF3B1
and
TP53
gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly,
SF3B1
mutated samples without concurrent
ATM
and
TP53
aberrations (sole
SF3B1
) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast,
NOTCH1
or
K/N-RAS
mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole
SF3B1
mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with
SF3B1
mutations.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2014.318</identifier><identifier>PMID: 25371178</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38/77 ; 45/23 ; 631/67/1990/283/1895 ; 82/80 ; Analysis ; Apoptosis ; Ataxia Telangiectasia Mutated Proteins - metabolism ; Cancer ; Cancer Research ; Care and treatment ; Chemotherapy ; Chronic lymphocytic leukemia ; Cohort Studies ; Critical Care Medicine ; Deoxyribonucleic acid ; Development and progression ; DNA ; DNA Damage ; DNA Mutational Analysis ; Doxorubicin - pharmacology ; Flow Cytometry ; Gene Deletion ; Gene expression ; Gene Expression Regulation, Leukemic ; Gene mutations ; Gene sequencing ; Genetic analysis ; Genetic aspects ; Genome, Human ; Genome-wide association studies ; Genomes ; Health aspects ; Hematology ; Histones - metabolism ; Humans ; Imidazoles - pharmacology ; Impact damage ; Intensive ; Internal Medicine ; Irradiation ; Kinases ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Lymphatic leukemia ; Medicine ; Medicine & Public Health ; Methods ; Mutation ; Oncology ; original-article ; p53 Protein ; Phosphoproteins - genetics ; Phosphorylation ; Piperazines - pharmacology ; Prognosis ; Radiation ; Radiation damage ; Receptor, Notch1 - genetics ; Ribonucleoprotein, U2 Small Nuclear - genetics ; RNA Splicing Factors ; Splicing factors ; Transcription ; Tumor Suppressor Protein p53 - genetics ; Vidarabine - analogs & derivatives ; Vidarabine - pharmacology</subject><ispartof>Leukemia, 2015-05, Vol.29 (5), p.1133-1142</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2015</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c683t-f8c46a9635ac18465ee480d5d98d91d772b07c1da26940884b6e9aa8f857fd93</citedby><cites>FETCH-LOGICAL-c683t-f8c46a9635ac18465ee480d5d98d91d772b07c1da26940884b6e9aa8f857fd93</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.2014.318$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2014.318$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25371178$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>te Raa, G D</creatorcontrib><creatorcontrib>Derks, I A M</creatorcontrib><creatorcontrib>Navrkalova, V</creatorcontrib><creatorcontrib>Skowronska, A</creatorcontrib><creatorcontrib>Moerland, P D</creatorcontrib><creatorcontrib>van Laar, J</creatorcontrib><creatorcontrib>Oldreive, C</creatorcontrib><creatorcontrib>Monsuur, H</creatorcontrib><creatorcontrib>Trbusek, M</creatorcontrib><creatorcontrib>Malcikova, J</creatorcontrib><creatorcontrib>Lodén, M</creatorcontrib><creatorcontrib>Geisler, C H</creatorcontrib><creatorcontrib>Hüllein, J</creatorcontrib><creatorcontrib>Jethwa, A</creatorcontrib><creatorcontrib>Zenz, T</creatorcontrib><creatorcontrib>Pospisilova, S</creatorcontrib><creatorcontrib>Stankovic, T</creatorcontrib><creatorcontrib>van Oers, M H J</creatorcontrib><creatorcontrib>Kater, A P</creatorcontrib><creatorcontrib>Eldering, E</creatorcontrib><title>The impact of SF3B1 mutations in CLL on the DNA-damage response</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Mutations or deletions in
TP53
or
ATM
are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with
ATM
aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (
n
=110) containing
ATM
,
SF3B1
and
TP53
gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly,
SF3B1
mutated samples without concurrent
ATM
and
TP53
aberrations (sole
SF3B1
) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast,
NOTCH1
or
K/N-RAS
mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole
SF3B1
mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with
SF3B1
mutations.</description><subject>38/77</subject><subject>45/23</subject><subject>631/67/1990/283/1895</subject><subject>82/80</subject><subject>Analysis</subject><subject>Apoptosis</subject><subject>Ataxia Telangiectasia Mutated Proteins - metabolism</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Chemotherapy</subject><subject>Chronic lymphocytic leukemia</subject><subject>Cohort Studies</subject><subject>Critical Care Medicine</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA Damage</subject><subject>DNA Mutational Analysis</subject><subject>Doxorubicin - pharmacology</subject><subject>Flow Cytometry</subject><subject>Gene Deletion</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Gene mutations</subject><subject>Gene sequencing</subject><subject>Genetic analysis</subject><subject>Genetic aspects</subject><subject>Genome, Human</subject><subject>Genome-wide association studies</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>Hematology</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Impact damage</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Irradiation</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</subject><subject>Lymphatic leukemia</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Methods</subject><subject>Mutation</subject><subject>Oncology</subject><subject>original-article</subject><subject>p53 Protein</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphorylation</subject><subject>Piperazines - pharmacology</subject><subject>Prognosis</subject><subject>Radiation</subject><subject>Radiation damage</subject><subject>Receptor, Notch1 - genetics</subject><subject>Ribonucleoprotein, U2 Small Nuclear - genetics</subject><subject>RNA Splicing Factors</subject><subject>Splicing factors</subject><subject>Transcription</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Vidarabine - analogs & derivatives</subject><subject>Vidarabine - pharmacology</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkk1vEzEQhi1ERUPhxhmthIQ4sMHj7z1VIdCCFMGB3C3Hnk222l2H9e6Bf49DCk1RBfbB0swz74xHLyEvgM6BcvOuxWnOKIg5B_OIzEBoVUop4TGZUWN0qSomzsnTlG4oPSTVE3LOJNcA2szI5XqHRdPtnR-LWBffrvh7KLppdGMT-1Q0fbFcrYrYF2PmPnxZlMF1bovFgGmfAXxGzmrXJnx--16Q9dXH9fJTufp6_Xm5WJVeGT6WtfFCuUpx6TwYoSSiMDTIUJlQQdCabaj2EBxTlchji43CyjlTG6nrUPEL8uYoux_i9wnTaLsmeWxb12OckoXchUvNlMjoq7_QmzgNfR7OMs5BMc3z-QcFShutKSh6R21di7bp6zgOzh9a24UAoSpuKGRq_gCVb8Cu8bHHusnxewWvTwp26Npxl2I7_dq5XSigjAqeB_0PeKr49gj6IaY0YG33Q9O54YcFag82sdkm9mATm22S8Ze3v582HYY_8G9fZKA8Aimn-i0OJ-t5SPAnawC-_g</recordid><startdate>20150501</startdate><enddate>20150501</enddate><creator>te Raa, G D</creator><creator>Derks, I A M</creator><creator>Navrkalova, V</creator><creator>Skowronska, A</creator><creator>Moerland, P D</creator><creator>van Laar, J</creator><creator>Oldreive, C</creator><creator>Monsuur, H</creator><creator>Trbusek, M</creator><creator>Malcikova, J</creator><creator>Lodén, M</creator><creator>Geisler, C H</creator><creator>Hüllein, J</creator><creator>Jethwa, A</creator><creator>Zenz, T</creator><creator>Pospisilova, S</creator><creator>Stankovic, T</creator><creator>van Oers, M H J</creator><creator>Kater, A P</creator><creator>Eldering, E</creator><general>Nature Publishing Group UK</general><general>Nature Publishing 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impact of SF3B1 mutations in CLL on the DNA-damage response</title><author>te Raa, G D ; Derks, I A M ; Navrkalova, V ; Skowronska, A ; Moerland, P D ; van Laar, J ; Oldreive, C ; Monsuur, H ; Trbusek, M ; Malcikova, J ; Lodén, M ; Geisler, C H ; Hüllein, J ; Jethwa, A ; Zenz, T ; Pospisilova, S ; Stankovic, T ; van Oers, M H J ; Kater, A P ; Eldering, E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c683t-f8c46a9635ac18465ee480d5d98d91d772b07c1da26940884b6e9aa8f857fd93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>38/77</topic><topic>45/23</topic><topic>631/67/1990/283/1895</topic><topic>82/80</topic><topic>Analysis</topic><topic>Apoptosis</topic><topic>Ataxia Telangiectasia Mutated Proteins - metabolism</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>Chemotherapy</topic><topic>Chronic lymphocytic leukemia</topic><topic>Cohort Studies</topic><topic>Critical Care Medicine</topic><topic>Deoxyribonucleic acid</topic><topic>Development and progression</topic><topic>DNA</topic><topic>DNA Damage</topic><topic>DNA Mutational Analysis</topic><topic>Doxorubicin - pharmacology</topic><topic>Flow Cytometry</topic><topic>Gene Deletion</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>Gene mutations</topic><topic>Gene sequencing</topic><topic>Genetic analysis</topic><topic>Genetic aspects</topic><topic>Genome, Human</topic><topic>Genome-wide association studies</topic><topic>Genomes</topic><topic>Health aspects</topic><topic>Hematology</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Impact damage</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Irradiation</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</topic><topic>Lymphatic leukemia</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Methods</topic><topic>Mutation</topic><topic>Oncology</topic><topic>original-article</topic><topic>p53 Protein</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphorylation</topic><topic>Piperazines - pharmacology</topic><topic>Prognosis</topic><topic>Radiation</topic><topic>Radiation damage</topic><topic>Receptor, Notch1 - genetics</topic><topic>Ribonucleoprotein, U2 Small Nuclear - genetics</topic><topic>RNA Splicing Factors</topic><topic>Splicing factors</topic><topic>Transcription</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Vidarabine - analogs & derivatives</topic><topic>Vidarabine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>te Raa, G D</creatorcontrib><creatorcontrib>Derks, I A M</creatorcontrib><creatorcontrib>Navrkalova, V</creatorcontrib><creatorcontrib>Skowronska, 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D</au><au>van Laar, J</au><au>Oldreive, C</au><au>Monsuur, H</au><au>Trbusek, M</au><au>Malcikova, J</au><au>Lodén, M</au><au>Geisler, C H</au><au>Hüllein, J</au><au>Jethwa, A</au><au>Zenz, T</au><au>Pospisilova, S</au><au>Stankovic, T</au><au>van Oers, M H J</au><au>Kater, A P</au><au>Eldering, E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The impact of SF3B1 mutations in CLL on the DNA-damage response</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2015-05-01</date><risdate>2015</risdate><volume>29</volume><issue>5</issue><spage>1133</spage><epage>1142</epage><pages>1133-1142</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Mutations or deletions in
TP53
or
ATM
are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with
ATM
aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (
n
=110) containing
ATM
,
SF3B1
and
TP53
gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly,
SF3B1
mutated samples without concurrent
ATM
and
TP53
aberrations (sole
SF3B1
) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast,
NOTCH1
or
K/N-RAS
mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole
SF3B1
mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with
SF3B1
mutations.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25371178</pmid><doi>10.1038/leu.2014.318</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2015-05, Vol.29 (5), p.1133-1142 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1683357264 |
| source | MEDLINE; SpringerLink Journals; Nature; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | 38/77 45/23 631/67/1990/283/1895 82/80 Analysis Apoptosis Ataxia Telangiectasia Mutated Proteins - metabolism Cancer Cancer Research Care and treatment Chemotherapy Chronic lymphocytic leukemia Cohort Studies Critical Care Medicine Deoxyribonucleic acid Development and progression DNA DNA Damage DNA Mutational Analysis Doxorubicin - pharmacology Flow Cytometry Gene Deletion Gene expression Gene Expression Regulation, Leukemic Gene mutations Gene sequencing Genetic analysis Genetic aspects Genome, Human Genome-wide association studies Genomes Health aspects Hematology Histones - metabolism Humans Imidazoles - pharmacology Impact damage Intensive Internal Medicine Irradiation Kinases Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - genetics Lymphatic leukemia Medicine Medicine & Public Health Methods Mutation Oncology original-article p53 Protein Phosphoproteins - genetics Phosphorylation Piperazines - pharmacology Prognosis Radiation Radiation damage Receptor, Notch1 - genetics Ribonucleoprotein, U2 Small Nuclear - genetics RNA Splicing Factors Splicing factors Transcription Tumor Suppressor Protein p53 - genetics Vidarabine - analogs & derivatives Vidarabine - pharmacology |
| title | The impact of SF3B1 mutations in CLL on the DNA-damage response |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T03%3A28%3A11IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20impact%20of%20SF3B1%20mutations%20in%20CLL%20on%20the%20DNA-damage%20response&rft.jtitle=Leukemia&rft.au=te%20Raa,%20G%20D&rft.date=2015-05-01&rft.volume=29&rft.issue=5&rft.spage=1133&rft.epage=1142&rft.pages=1133-1142&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/leu.2014.318&rft_dat=%3Cgale_proqu%3EA610204327%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1678770160&rft_id=info:pmid/25371178&rft_galeid=A610204327&rfr_iscdi=true |