Sox4 is a key oncogenic target in C/EBP mutant Acute Myeloid Leukemia

Mutation or epigenetic silencing of the transcription factor C/EBP is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBP whereby its expression is inversely correlated with C/EBP 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 mutant C/EBP AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBP inactivation contributes to the development of leukemias with a distinct LIC phenotype.

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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