Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia

Area of Science:

• Hematology
• Molecular Biology
• Genomics

Background:

• inv(3)/t(3;3) chromosomal rearrangements in myeloid leukemias are linked to EVI1 upregulation.
• SF3B1 mutations are frequently co-occurring in inv(3)/t(3;3) myeloid neoplasms.

Purpose of the Study:

• To identify and characterize a novel oncogenic EVI1 isoform in inv(3)/t(3;3) AML.
• To elucidate the role of SF3B1 mutations in generating this EVI1 isoform and driving leukemogenesis.

Main Methods:

• Genomic and epigenomic analyses of MECOM locus.
• Identification and characterization of a novel EVI1 splice variant.
• Mutation analysis of SF3B1 in patient samples and cell lines.
• In vivo studies using mouse models with humanized inv(3)(q21q26) allele and mutant SF3B1.

Main Results:

• A novel, previously unannotated EVI1 isoform is generated by SF3B1 mutations in inv(3)/t(3;3) AML.
• This isoform results from an in-frame 6 amino acid insertion in EVI1 due to aberrant splicing.
• SF3B1 mutations promote this aberrant splicing by utilizing a cryptic branch point and alternative splice site.
• Expression of the EVI1 splice variant enhances hematopoietic stem cell self-renewal.
• Mutant SF3B1 accelerates leukemogenesis in vivo in a mouse model.

Conclusions:

• SF3B1 mutations are a key driver in generating an oncogenic EVI1 splice variant in inv(3)/t(3;3) myeloid leukemias.
• This novel EVI1 isoform contributes mechanistically to leukemic transformation.
• These findings provide new insights into the pathogenesis of inv(3)/t(3;3) myeloid neoplasms.