PRDM15 is a master regulator of metabolism essential to sustain B-cell lymphomagenesis

PRDM family members are sequence-specific transcriptional regulators involved in cell identity and fate determination and are often dysregulated in cancer. The PRDM15 gene is of particular interest, given its relatively low expression in adult tissues and its overexpression in follicular lymphomas (FL). Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays an essential role in B cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program pertinent to the activity of the PI3K/AKT/mTOR pathway and glycolysis in B cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.