Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia.
Zhang H., Alberich-Jorda M., Amabile G., Yang H., Staber PB., Di Ruscio A., Welner RS., Ebralidze A., Zhang J., Levantini E., Lefebvre V., Valk PJ., Delwel R., Hoogenkamp M., Nerlov C., Cammenga J., Saez B., Scadden DT., Bonifer C., Ye M., Tenen DG.
Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ∼10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia-initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.