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

by Selleckchem | Sep 07 2023

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 particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium 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 pathognomonic 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 equilibrium 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 leukemogenesis, 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.

Comments:

The passage you provided describes a proposed mechanism for the development of myeloid leukemia associated with Down syndrome (ML-DS). ML-DS is characterized by an increased risk of leukemia in individuals with Down syndrome (trisomy 21). The researchers suggest that an imbalance of different isoforms of the RUNX1 gene, particularly an elevation in the RUNX1A isoform, plays a crucial role in the development of ML-DS.

The researchers conducted CRISPR-Cas9 screens focused on chromosome 21 and identified a strong dependence on the RUNX1 gene in ML-DS cells. They found that ML-DS patients exhibited elevated expression of the RUNX1A isoform. Using mouse models and patient-derived xenografts, they demonstrated that an excess of RUNX1A, in conjunction with the Gata1s mutation commonly found in ML-DS, promotes leukemogenesis by displacing another isoform of RUNX1, RUNX1C, from its normal binding sites. The excess RUNX1A then forms a complex with the MYC cofactor MAX, leading to the activation of oncogenic programs.

The researchers were able to reverse these effects by restoring the balance between RUNX1A and RUNX1C in patient-derived xenografts, both in vitro and in vivo. Furthermore, they found that interfering with the interaction between MYC and MAX using a pharmacological inhibitor called MYCi361 exerted strong anti-leukemic effects.

This study highlights the significance of alternative splicing in the development of leukemia, particularly in the context of aneuploidy. It also suggests potential avenues for the development of targeted therapies for ML-DS and other leukemias associated with aneuploidy of chromosome 21 or an imbalance of RUNX1 isoforms.