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

Slim Mzoughi, Jia Yi Fong, David Papadopoli, Cheryl M. Koh, Laura Hulea, Paolo Pigini, Federico Tullio, Giuseppe Andreacchio, Michal Marek Hoppe, Heike Wollmann, Diana Low, Matias J. Caldez, Yanfen Peng, Denis Torre, Julia N. Zhao, Oro Uchenunu, Gabriele Varano, Corina-Mihaela Motofeanu, Manikandan Lakshmanan, Shun Xie Teo, Cheng Mun Wun, Giovanni Perini, Soo Yong Tan, Chee Bing Ong, Muthafar Al-Haddawi, Ravisankar Rajarethinam, Susan Swee-Shan Hue, Soon Thye Lim, Choon Kiat Ong, Dachuan Huang, Siok-Bian Ng, Emily Bernstein, Dan Hasson, Keng Boon Wee, Philipp Kaldis, Anand Jeyasekharan, David Dominguez-sola, Ivan Topisirovic () and Ernesto Guccione ()
Additional contact information
Slim Mzoughi: Agency for Science, Technology and Research (A*STAR)
Jia Yi Fong: Agency for Science, Technology and Research (A*STAR)
David Papadopoli: McGill University
Cheryl M. Koh: Agency for Science, Technology and Research (A*STAR)
Laura Hulea: McGill University
Paolo Pigini: Agency for Science, Technology and Research (A*STAR)
Federico Tullio: Agency for Science, Technology and Research (A*STAR)
Giuseppe Andreacchio: Agency for Science, Technology and Research (A*STAR)
Michal Marek Hoppe: National University of Singapore
Heike Wollmann: Agency for Science, Technology and Research (A*STAR)
Diana Low: Agency for Science, Technology and Research (A*STAR)
Matias J. Caldez: Agency for Science, Technology and Research (A*STAR)
Yanfen Peng: National University of Singapore
Denis Torre: Icahn School of Medicine at Mount Sinai
Julia N. Zhao: Icahn School of Medicine at Mount Sinai
Oro Uchenunu: McGill University
Gabriele Varano: Icahn School of Medicine at Mount Sinai
Corina-Mihaela Motofeanu: Agency for Science, Technology and Research (A*STAR)
Manikandan Lakshmanan: Agency for Science, Technology and Research (A*STAR)
Shun Xie Teo: Agency for Science, Technology and Research (A*STAR)
Cheng Mun Wun: Agency for Science, Technology and Research (A*STAR)
Giovanni Perini: University of Bologna
Soo Yong Tan: Agency for Science, Technology and Research (A*STAR)
Chee Bing Ong: Agency for Science, Technology and Research (A*STAR)
Muthafar Al-Haddawi: Agency for Science, Technology and Research (A*STAR)
Ravisankar Rajarethinam: Agency for Science, Technology and Research (A*STAR)
Susan Swee-Shan Hue: Agency for Science, Technology and Research (A*STAR)
Soon Thye Lim: National Cancer Centre Singapore
Choon Kiat Ong: Duke-NUS Graduate Medical School
Dachuan Huang: National Cancer Centre Singapore
Siok-Bian Ng: National University of Singapore
Emily Bernstein: Icahn School of Medicine at Mount Sinai
Dan Hasson: Icahn School of Medicine at Mount Sinai
Keng Boon Wee: Agency for Science, Technology and Research (A*STAR)
Philipp Kaldis: Agency for Science, Technology and Research (A*STAR)
Anand Jeyasekharan: National University of Singapore
David Dominguez-sola: Icahn School of Medicine at Mount Sinai
Ivan Topisirovic: McGill University
Ernesto Guccione: Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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 largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains 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.

Date: 2020
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DOI: 10.1038/s41467-020-17064-0

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