RUNX1 isoform disequilibrium promotes the development of trisomy 21-associated myeloid leukemia

Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are partic-ularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequi-librium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR-CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the patho-gnomonic Gata1s mutation during 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 equilib-rium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogen-esis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

Automated summary

It is proposed that the imbalance of the RUNX1 isoform, with a bias towards RUNX1A, is key to the development of myeloid leukemia in individuals with Down syndrome. Excess RUNX1A in combination with the Gata1s mutation displaces RUNX1C and induces oncogenic programs with the MYC cofactor MAX, an effect that can be reversed by restoring the balance between RUNX1A and RUNX1C. Additionally, targeting MYC:MAX dimerization shows strong anti-leukemic effects.