Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia [mouse_RNA-seq]

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 at MECOM drive inv(3)/t(3;3) myeloid leukemias and revealed MECOM germline mutations in patients with MECOM-associated bone marrow failure syndromes. Here we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 which is frequently present in inv(3)/t(3;3) AML and directly contributes to leukemic transformation. 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)(q21;26) allele hastened leukemogenesis in vivo. These data provide a mechanistic basis for the frequent co-occurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3). Overall design: 1.0 x 10E6 total BM cells of Mx1-Cre control, Mx1-Cre inv(3), Mx1-Cre Sf3b1K700E/WT, and Mx1-Cre inv(3) Sf3b1K700E/WT CD45.2+ mice were mixed with 1.0 x 10E6 WT CD45.1+ support BM and transplanted via tail vein injection into lethally irradiated (two times 450 cGy) CD45.1+ recipient mice. Four weeks after BMT, the recipient mice received 20 mg/kg pIpC injection every other day for a total of 3 doses. Six months after pIpC injection, the recipient mice were sacrificed for sample preparation.