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 Di 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; Ernesto Guccione

doi:10.1038/s41467-020-17064-0

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 Di 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 TeoCheng 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, Ernesto Guccione

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22 Scopus citations

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.

Original language	English
Article number	3520
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17064-0
State	Published - 1 Dec 2020

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Mzoughi, S., Fong, J. Y., Papadopoli, D., Koh, C. M., Hulea, L., Pigini, P., Di Tullio, F., Andreacchio, G., Hoppe, M. M., Wollmann, H., Low, D., Caldez, M. J., Peng, Y., Torre, D., Zhao, J. N., Uchenunu, O., Varano, G., Motofeanu, C. M., Lakshmanan, M., ... Guccione, E. (2020). PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis. Nature Communications, 11(1), Article 3520. https://doi.org/10.1038/s41467-020-17064-0

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title = "PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis",

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.",

author = "Slim Mzoughi and Fong, {Jia Yi} and David Papadopoli and Koh, {Cheryl M.} and Laura Hulea and Paolo Pigini and {Di Tullio}, Federico and Giuseppe Andreacchio and Hoppe, {Michal Marek} and Heike Wollmann and Diana Low and Caldez, {Matias J.} and Yanfen Peng and Denis Torre and Zhao, {Julia N.} and Oro Uchenunu and Gabriele Varano and Motofeanu, {Corina Mihaela} and Manikandan Lakshmanan and Teo, {Shun Xie} and Wun, {Cheng Mun} and Giovanni Perini and Tan, {Soo Yong} and Ong, {Chee Bing} and Muthafar Al-Haddawi and Ravisankar Rajarethinam and Hue, {Susan Swee Shan} and Lim, {Soon Thye} and Ong, {Choon Kiat} and Dachuan Huang and Ng, {Siok Bian} and Emily Bernstein and Dan Hasson and Wee, {Keng Boon} and Philipp Kaldis and Anand Jeyasekharan and David Dominguez-sola and Ivan Topisirovic and Ernesto Guccione",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

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Mzoughi, S, Fong, JY, Papadopoli, D, Koh, CM, Hulea, L, Pigini, P, Di Tullio, F, Andreacchio, G, Hoppe, MM, Wollmann, H, Low, D, Caldez, MJ, Peng, Y, Torre, D, Zhao, JN, Uchenunu, O, Varano, G, Motofeanu, CM, Lakshmanan, M, Teo, SX, Wun, CM, Perini, G, Tan, SY, Ong, CB, Al-Haddawi, M, Rajarethinam, R, Hue, SSS, Lim, ST, Ong, CK, Huang, D, Ng, SB, Bernstein, E, Hasson, D, Wee, KB, Kaldis, P, Jeyasekharan, A, Dominguez-sola, D, Topisirovic, I & Guccione, E 2020, 'PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis', Nature Communications, vol. 11, no. 1, 3520. https://doi.org/10.1038/s41467-020-17064-0

TY - JOUR

T1 - PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis

AU - Mzoughi, Slim

AU - Fong, Jia Yi

AU - Papadopoli, David

AU - Koh, Cheryl M.

AU - Hulea, Laura

AU - Pigini, Paolo

AU - Di Tullio, Federico

AU - Andreacchio, Giuseppe

AU - Hoppe, Michal Marek

AU - Wollmann, Heike

AU - Low, Diana

AU - Caldez, Matias J.

AU - Peng, Yanfen

AU - Torre, Denis

AU - Zhao, Julia N.

AU - Uchenunu, Oro

AU - Varano, Gabriele

AU - Motofeanu, Corina Mihaela

AU - Lakshmanan, Manikandan

AU - Teo, Shun Xie

AU - Wun, Cheng Mun

AU - Perini, Giovanni

AU - Tan, Soo Yong

AU - Ong, Chee Bing

AU - Al-Haddawi, Muthafar

AU - Rajarethinam, Ravisankar

AU - Hue, Susan Swee Shan

AU - Lim, Soon Thye

AU - Ong, Choon Kiat

AU - Huang, Dachuan

AU - Ng, Siok Bian

AU - Bernstein, Emily

AU - Hasson, Dan

AU - Wee, Keng Boon

AU - Kaldis, Philipp

AU - Jeyasekharan, Anand

AU - Dominguez-sola, David

AU - Topisirovic, Ivan

AU - Guccione, Ernesto

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-020-17064-0

DO - 10.1038/s41467-020-17064-0

M3 - Article

C2 - 32665551

AN - SCOPUS:85087990243

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3520

ER -

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

Abstract

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