Mechanisms driving the increase in cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed toward increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates ( and as growth suppressors and as a driver) and successfully validated their causal growth effects by overexpression in mouse leukemic cells. Overexpression of the gene in human MOLM13 leukemic cells suppressed cell growth both in vitro and in mouse xenografts. Public patient data confirmed expression levels of and as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML. © 2026 Bonilla et al.; Published by Cold Spring Harbor Laboratory Press.