RUNX1 isoform disequilibrium in the development of trisomy 21 associated myeloid leukemia

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.

Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model

“…Here, we showed that low-dose BET inhibitor treatment inhibits both proliferation and survival of megakaryoblasts. Our data suggest that the MYC pathway is a major and targetable pathway in DS-AMKL and are consistent with a recent study showing that MYC inhibition induces apoptosis of DS-AMKL blasts ( 46 ).…”

“…Notably, the SMC3 +/– -dependent gain in RUNX1/ETS binding site accessibility in T21 MKs may synergize with the previously reported loss of interaction between RB1 and GATA1s ( 44 ). An increased level of MYC and of MYC activity in DS-AMKL in comparison with other pediatric AMKL has been previously reported ( 45 ), and recently it has been reported that it is related to an excess of RUNX1A isoform ( 46 ). Here, we showed that low-dose BET inhibitor treatment inhibits both proliferation and survival of megakaryoblasts.…”