Histone Methyltransferase NSD2 Activates PKCα to Drive Metabolic Reprogramming and Lenalidomide Resistance in Multiple Myeloma

Author:

Chong Phyllis S.Y.12ORCID,Chooi Jing-Yuan1ORCID,Lim Julia S.L.12ORCID,Leow Aaron C.Y.2ORCID,Toh Sabrina Hui Min2ORCID,Azaman Irfan2ORCID,Koh Mun Yee1ORCID,Teoh Phaik Ju12ORCID,Tan Tuan Zea2ORCID,Chung Tae-Hoon2ORCID,Chng Wee Joo123ORCID

Affiliation:

1. 1Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

2. 2Cancer Science Institute of Singapore, National University of Singapore, Singapore.

3. 3Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.

Abstract

Abstract Multiple myeloma cells undergo metabolic reprogramming in response to the hypoxic and nutrient-deprived bone marrow microenvironment. Primary oncogenes in recurrent translocations might be able to drive metabolic heterogeneity to survive the microenvironment that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase NSD2 that promotes plasma cell transformation through a global increase in H3K36me2. Here, we identified PKCα as an epigenetic target that contributes to the oncogenic potential of NSD2. RNA sequencing of t(4;14) multiple myeloma cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCα, and the glycolytic gene, hexokinase 2 (HK2), was transcriptionally regulated by PKCα in a PI3K/Akt-dependent manner. Loss of PKCα displaced mitochondria-bound HK2 and reversed sensitivity to the glycolytic inhibitor 3-bromopyruvate. In addition, the perturbation of glycolytic flux led to a metabolic shift to a less energetic state and decreased ATP production. Metabolomics analysis indicated lactate as a differential metabolite associated with PKCα. As a result, PKCα conferred resistance to the immunomodulatory drugs (IMiD) lenalidomide in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Clinically, t(4;14) patients had elevated plasma lactate levels and did not benefit from lenalidomide-based regimens. Altogether, this study provides insights into the epigenetic-metabolism cross-talk in multiple myeloma and highlights the opportunity for therapeutic intervention that leverages the distinct metabolic program in t(4;14) myeloma. Significance: Aberrant glycolysis driven by NSD2-mediated upregulation of PKCα can be therapeutically exploited using metabolic inhibitors with lactate as a biomarker to identify high-risk patients who exhibit poor response towards IMiD-based regimens.

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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