Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia

Atsushi Tanaka, Taizo A. Nakano, Masaki Nomura, Hiromi Yamazaki, Jan P. Bewersdorf, Roger Mulet-Lazaro, Simon Hogg, Bo Liu, Alex Penson, Akihiko Yokoyama, Weijia Zang, Marije Havermans, Miho Koizumi, Yasutaka Hayashi, Hana Cho, Akinori Kanai, Stanley C. Lee, Muran Xiao, Yui Koike, Yifan ZhangMiki Fukumoto, Yumi Aoyama, Tsuyoshi Konuma, Hiroyoshi Kunimoto, Toshiya Inaba, Hideaki Nakajima, Hiroaki Honda, Hiroshi Kawamoto, Ruud Delwel, Omar Abdel-Wahab*, Daichi Inoue

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3′ end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3′ splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

Original languageEnglish
Pages (from-to)875-888
Number of pages14
JournalBlood
Volume140
Issue number8
DOIs
Publication statusPublished - 25 Aug 2022

Fingerprint

Dive into the research topics of 'Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia'. Together they form a unique fingerprint.

Cite this