Abstract

Mechanisms driving cell growth during clonal evolution in leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in independent leukemic clones evolving towards increased growth. The evolved subclones lost their growth differential ex vivo but restored it upon secondary transplantation, suggesting molecular memory of their evolutionary stage. Genome-wide, clonal evolution was associated with clone-specific gradual modulation of chromatin states and expression levels, with a surprising preferential trend of reversing the prior changes observed at the early leukemic stage. We leveraged clonal specificity of these modulation patterns to focus on the core gene set of potential growth regulators with consistent changes of expression and chromatin marks that were maintained in vivo and ex vivo in both independent clones. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and validated their predicted growth effects by overexpression in leukemic subclones. AML patient data confirmed IRX5 and SMAD1 as markers of AML status in patients, suggesting that multiomic analysis of clonal evolution in a mouse model is a valuable predictive approach relevant to human AML.