SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition

Eunhee Kim; Janine O. Ilagan; Yang Liang; Gerrit M. Daubner; Stanley C.W. Lee; Aravind Ramakrishnan; Yue Li; Young Rock Chung; Jean Baptiste Micol; Michele E. Murphy; Hana Cho; Min Kyung Kim; Ahmad S. Zebari; Shlomzion Aumann; Christopher Y. Park; Silvia Buonamici; Peter G. Smith; H. Joachim Deeg; Camille Lobry; Iannis Aifantis; Yorgo Modis; Frederic H.T. Allain; Stephanie Halene; Robert K. Bradley; Omar Abdel-Wahab

doi:10.1016/j.ccell.2015.04.006

SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition

Eunhee Kim, Janine O. Ilagan, Yang Liang, Gerrit M. Daubner, Stanley C.W. Lee, Aravind Ramakrishnan, Yue Li, Young Rock Chung, Jean Baptiste Micol, Michele E. Murphy, Hana Cho, Min Kyung Kim, Ahmad S. Zebari, Shlomzion Aumann, Christopher Y. Park, Silvia Buonamici, Peter G. Smith, H. Joachim Deeg, Camille Lobry, Iannis AifantisYorgo Modis, Frederic H.T. Allain, Stephanie Halene, Robert K. Bradley, Omar Abdel-Wahab

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Résumé

Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.

langue originale	Anglais
Pages (de - à)	617-630
Nombre de pages	14
journal	Cancer Cell
Volume	27
Numéro de publication	5
Les DOIs	https://doi.org/10.1016/j.ccell.2015.04.006
état	Publié - 11 mai 2015
Modification externe	Oui

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10.1016/j.ccell.2015.04.006

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Kim, E., Ilagan, J. O., Liang, Y., Daubner, G. M., Lee, S. C. W., Ramakrishnan, A., Li, Y., Chung, Y. R., Micol, J. B., Murphy, M. E., Cho, H., Kim, M. K., Zebari, A. S., Aumann, S., Park, C. Y., Buonamici, S., Smith, P. G., Deeg, H. J., Lobry, C., ... Abdel-Wahab, O. (2015). SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer Cell, 27(5), 617-630. https://doi.org/10.1016/j.ccell.2015.04.006

@article{41e54a16cc664d0aab58fc88304bc94f,

title = "SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition",

abstract = "Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.",

author = "Eunhee Kim and Ilagan, {Janine O.} and Yang Liang and Daubner, {Gerrit M.} and Lee, {Stanley C.W.} and Aravind Ramakrishnan and Yue Li and Chung, {Young Rock} and Micol, {Jean Baptiste} and Murphy, {Michele E.} and Hana Cho and Kim, {Min Kyung} and Zebari, {Ahmad S.} and Shlomzion Aumann and Park, {Christopher Y.} and Silvia Buonamici and Smith, {Peter G.} and Deeg, {H. Joachim} and Camille Lobry and Iannis Aifantis and Yorgo Modis and Allain, {Frederic H.T.} and Stephanie Halene and Bradley, {Robert K.} and Omar Abdel-Wahab",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = may,

day = "11",

doi = "10.1016/j.ccell.2015.04.006",

language = "English",

volume = "27",

pages = "617--630",

journal = "Cancer Cell",

issn = "1535-6108",

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Kim, E, Ilagan, JO, Liang, Y, Daubner, GM, Lee, SCW, Ramakrishnan, A, Li, Y, Chung, YR, Micol, JB, Murphy, ME, Cho, H, Kim, MK, Zebari, AS, Aumann, S, Park, CY, Buonamici, S, Smith, PG, Deeg, HJ, Lobry, C, Aifantis, I, Modis, Y, Allain, FHT, Halene, S, Bradley, RK & Abdel-Wahab, O 2015, 'SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition', Cancer Cell, VOL. 27, Numéro 5, p. 617-630. https://doi.org/10.1016/j.ccell.2015.04.006

TY - JOUR

T1 - SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition

AU - Kim, Eunhee

AU - Ilagan, Janine O.

AU - Liang, Yang

AU - Daubner, Gerrit M.

AU - Lee, Stanley C.W.

AU - Ramakrishnan, Aravind

AU - Li, Yue

AU - Chung, Young Rock

AU - Micol, Jean Baptiste

AU - Murphy, Michele E.

AU - Cho, Hana

AU - Kim, Min Kyung

AU - Zebari, Ahmad S.

AU - Aumann, Shlomzion

AU - Park, Christopher Y.

AU - Buonamici, Silvia

AU - Smith, Peter G.

AU - Deeg, H. Joachim

AU - Lobry, Camille

AU - Aifantis, Iannis

AU - Modis, Yorgo

AU - Allain, Frederic H.T.

AU - Halene, Stephanie

AU - Bradley, Robert K.

AU - Abdel-Wahab, Omar

PY - 2015/5/11

Y1 - 2015/5/11

N2 - Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.

AB - Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.

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U2 - 10.1016/j.ccell.2015.04.006

DO - 10.1016/j.ccell.2015.04.006

M3 - Article

C2 - 25965569

AN - SCOPUS:84929162813

SN - 1535-6108

VL - 27

SP - 617

EP - 630

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -