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

ABSTRACT: 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.

INSTRUMENT(S): Liquid Chromatography MS -, Gas Chromatography MS -

PROVIDER: MTBLS1639 | MetaboLights | 2025-06-16

REPOSITORIES: MetaboLights

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PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis.

Mzoughi Slim S Fong Jia Yi JY Papadopoli David D Koh Cheryl M CM Hulea Laura L Pigini Paolo P Di Tullio Federico F Andreacchio Giuseppe G Hoppe Michal Marek MM Wollmann Heike H Low Diana D Caldez Matias J MJ Peng Yanfen Y Torre Denis D Zhao Julia N JN Uchenunu Oro O Varano Gabriele G Motofeanu Corina-Mihaela CM Lakshmanan Manikandan M Teo Shun Xie SX Wun Cheng Mun CM Perini Giovanni G Tan Soo Yong SY Ong Chee Bing CB Al-Haddawi Muthafar M Rajarethinam Ravisankar R Hue Susan Swee-Shan SS Lim Soon Thye ST Ong Choon Kiat CK Huang Dachuan D Ng Siok-Bian SB Bernstein Emily E Hasson Dan D Wee Keng Boon KB Kaldis Philipp P Jeyasekharan Anand A Dominguez-Sola David D Topisirovic Ivan I Guccione Ernesto E

Nature communications 20200714 1

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. 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 ...[more]

PMID: 32665551

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Project description:Version 1. Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of the de novo diagnoses and also arising as a frequent clinical evolution of Follicular Lymphoma (FL). The molecular pathogenesis of DLBCL is associated with multiple genetic lesions that in part distinctly segregate with individual phenotypic subtypes, suggesting the involvement of distinct oncogenic pathways. However, the lesions identified so far likely represent only a fraction of those necessary for malignant transformation. In order to characterize the entire set of structural alterations present in the DLBCL genome, we have integrated next generation whole exome sequencing analysis of 6 DLBCL cases and genome-wide high-density SNP array analysis of 72 DLBCL cases. We report here that FL and DLBCL harbor frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signaling pathways. Overall, ~37% of DLBCL and 36% of FL cases display genomic deletions and/or somatic point mutations that remove or inactivate the HAT coding domain of these two genes. These lesions commonly affect a single allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in the acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumor suppressor. These results identify CREBBP/EP300 mutations as a major pathogenic mechanism shared by common forms of B-NHL, and have direct implications for the use of drugs targeting acetylation/deacetylation mechanisms. Version 2. Follicular lymphoma (FL) is an indolent, but incurable disease that, in 30-40% of cases, undergoes transformation to an aggressive diffuse large B cell lymphoma (DLBCL). The history of clonal evolution and the mechanisms that underlie transformation to DLBCL (tFL) remain largely unknown. Using whole exome sequencing and copy number analysis of 39 tFL patients, including 12 with paired sequential FL/tFL biopsies, we show that, in most cases, FL and tFL arise by divergent evolution from a common mutated precursor cell through the acquisition of distinct genetic lesions. Mutations in epigenetic modifiers (e.g., MLL2, CREBBP, EZH2, ARID1A) and anti-apoptotic genes (BCL2, FAS) were observed in 93% (36/39) and 78% (30/39) of cases, respectively, and were invariably shared between the two disease phases, suggesting an early acquisition in the common mutated precursor. Conversely, the development of tFL is associated with deregulation of genes involved in the control of cell proliferation, cell cycle progression and DNA damage responses (CDKN2A/2B, MYC, TP53), as well as with an aberrant activity of the somatic hypermutation mechanism. Finally, we show that the genomic profile of tFL shares significant similarities with that of germinal center B-cell type de novo DLBCL, but also displays unique combinations of altered genes that may explain the dismal clinical course of tFL.

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