Abstract

Aneuploidy is a hallmark of cancer, but its complex nature limits our understanding of how it drives oncogenesis. Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia and is associated with markedly increased leukemia risk. Here, we propose that disequilibrium of the RUNX1 isoforms is key to the pathogenesis of trisomy 21 (i.e. Down syndrome)-associated myeloid leukemia (ML-DS). Hsa21-focused CRISPR-Cas9 screens uncovered a strong and specific RUNX1 dependency in ML-DS. Mechanistic studies revealed that excess of RUNX1A isoform - as seen in ML-DS patients - synergized with the pathognomonic Gata1s mutation in leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium or pharmacological interference with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidies, and opens new avenues for developing specific and targeted therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/483334v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@16c5a95org.highwire.dtl.DTLVardef@af0ec7org.highwire.dtl.DTLVardef@f36bcborg.highwire.dtl.DTLVardef@129e832_HPS_FORMAT_FIGEXP M_FIG C_FIG