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特別講演2 小川誠司

"Whole exome sequencing reveals novel pathway mutations of splicing machinery in myelodysplasia"


(東京大学医科学研究所 幹細胞治療研究センター)



MDS and related disorders comprise a group of myeloid neoplasms characterized by deregulated blood cell production and a predisposition to AML1.  Currently, a number of gene mutations and cytogenetic changes have been implicated in the pathogenesis of MDS2.  However, mutations of this set of genes do not fully explain the pathogenesis of MDS because they are also found in other myeloid malignancies and roughly 20% of MDS cases have no known genetic changes.  So, in order to clarify a complete registry of gene mutations in MDS and identify those discriminate MDS from other myeloid neoplasm, we performed whole-exome sequencing of 29 cases showing myelodysplasia3.  A total of 268 somatic mutations were identified.  Among these 33 occurred in recurrent gene targets, which not only included a spectrum of known gene targets in MDS, but also affected previously unknown the genes that are mapped to the RNA splicing pathway, including U2AF35, SRSF2 and ZRSR2.  Together with additional three found in single cases, 16 (55.2%) of the 29 discovery cases carried a mutation affecting the component of the splicing machinery.  In a large series analysis, these splicing pathway mutations were frequent (~45 to ~85 %) in, and highly specific to myeloid neoplasms showing features of myelodysplasia.  Conspicuously, these mutations occurred in an almost completely mutually exclusive manner among mutated cases, and commonly affected the components of the splicing complex engaged in the 3' splice site recognition during RNA splicing, leading to production of unspliced or aberrantly spliced RNA species.  In fact, when transduced into HeLa cells, the S34F U2AF35 mutant resulted in the increased production of unspliced RNA species and elicited activation of the nonsense mediated decay pathway as revealed by RNA sequencing studies.  The U2AF35 mutants lead to suppression of cell growth with a G2/M cell cycle arrest and increased apoptosis and when introduced into mouse stem cells and transplanted into lethaly irradiated mice, resulted in reduced chimerism.  In conclusion, whole-exome sequencing unexpectedly revealed the high frequency of the splicing pathway mutations that are highly specific to MDS and related myeloid neoplasms, provideding the first evidence indicating that compromised RNA splicing by gene mutations are responsible for human pathogenesis.


1.     Corey SJ, Minden MD, Barber DL, Kantarjian H, Wang JC, Schimmer AD. Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer 2007;7:118-129.

2.     Bejar R, Levine R, Ebert BL. Unraveling the molecular pathophysiology of myelodysplastic syndromes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011;29:504-515.

3.     Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011;478:64-69.

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