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Aberrant EVI1splicing contributes to EVI1-rearranged leukemia

Authors :
Tanaka, Atsushi
Nakano, Taizo A.
Nomura, Masaki
Yamazaki, Hiromi
Bewersdorf, Jan P.
Mulet-Lazaro, Roger
Hogg, Simon
Liu, Bo
Penson, Alex
Yokoyama, Akihiko
Zang, Weijia
Havermans, Marije
Koizumi, Miho
Hayashi, Yasutaka
Cho, Hana
Kanai, Akinori
Lee, Stanley C.
Xiao, Muran
Koike, Yui
Zhang, Yifan
Fukumoto, Miki
Aoyama, Yumi
Konuma, Tsuyoshi
Kunimoto, Hiroyoshi
Inaba, Toshiya
Nakajima, Hideaki
Honda, Hiroaki
Kawamoto, Hiroshi
Delwel, Ruud
Abdel-Wahab, Omar
Inoue, Daichi
Source :
Blood; 20240101, Issue: Preprints
Publication Year :
2024

Abstract

Detailed genomic and epigenomic analyses of MECOM(the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drive inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer which upregulates transcription of EVI1. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1which is frequently present in inv(3)/t(3;3) 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 co-occurring genomic alteration in inv(3)/t(3;3) patients. SF3B1mutations 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 six 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 EVI1exon 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 co-occurrence of SF3B1mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

Details

Language :
English
ISSN :
00064971 and 15280020
Issue :
Preprints
Database :
Supplemental Index
Journal :
Blood
Publication Type :
Periodical
Accession number :
ejs60214917
Full Text :
https://doi.org/10.1182/blood.2021015325