Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia Journal Article

   


Authors: Tanaka, A.; Nakano, T. A.; Nomura, M.; Yamazaki, H.; Bewersdorf, J. P.; Mulet-Lazaro, R.; Hogg, S.; Liu, B.; Penson, A.; Yokoyama, A.; Zang, W.; Havermans, M.; Koizumi, M.; Hayashi, Y.; Cho, H.; Kanai, A.; Lee, S. C.; Xiao, M.; Koike, Y.; Zhang, Y.; Fukumoto, M.; Aoyama, Y.; Konuma, T.; Kunimoto, H.; Inaba, T.; Nakajima, H.; Honda, H.; Kawamoto, H.; Delwel, R.; Abdel-Wahab, O.; Inoue, D.
Article Title: Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia
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). © 2022 American Society of Hematology
Keywords: adult; controlled study; dna binding protein; gene mutation; human cell; exon; genetics; dna-binding proteins; leukemia, myeloid, acute; pathogenesis; nonhuman; cancer patient; animal cell; mouse; animal; metabolism; animals; mice; allele; proto oncogene; animal experiment; animal model; intron; transcription factor; in vivo study; pathology; transcription factors; gene rearrangement; leukemogenesis; hematopoietic stem cell; spliceosome; chromosome 3; chromosomes, human, pair 3; enhancer region; proto-oncogenes; acute myeloid leukemia; chromosome inversion; humans; human; male; article; stem cell self-renewal; rna splicing factor; hek293t cell line; protein splicing; mds1 and evi1 complex locus protein
Journal Title: Blood
Volume: 140
Issue: 8
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2022-08-25
Start Page: 875
End Page: 888
Language: English
DOI: 10.1182/blood.2021015325
PUBMED: 35709354
PROVIDER: scopus
PMCID: PMC9412007
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85136592570&doi=10.1182%2fblood.2021015325&partnerID=40&md5=ac97a2d0c4f49ba894056dd740d63065
Notes: Article -- Export Date: 3 October 2022 -- Source: Scopus
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MSK Authors
  1. Omar Ibrahim Abdel-Wahab
    586 Abdel-Wahab
  2. Hana Cho
    21 Cho
  3. Alexander Vincent Penson
    54 Penson
  4. Bo Liu
    25 Liu
  5. Simon John Hogg
    26 Hogg
  6. Jan Philipp Bewersdorf
    103 Bewersdorf
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