Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms.

Vasundhara Sharma,Kenneth L Wright,Pearlie K Epling-Burnette,Gary W Reuther

doi:10.3389/fimmu.2020.604142

Abstract

The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are associated with clonal myelopoiesis, elevated risk of death due to thrombotic complications, and transformation to acute myeloid leukemia (AML). JAK2 inhibitors improve the quality of life for MPN patients, but these approved therapeutics do not readily reduce the natural course of disease or antagonize the neoplastic clone. An understanding of the molecular and cellular changes requisite for MPN development and progression are needed to develop improved therapies. Recently, murine MPN models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on glucose. Neoplastic hematopoietic progenitor cells in these mice express elevated levels of glycolytic enzymes and exhibit enhanced levels of glycolysis and oxidative phosphorylation, and the disease phenotype of these MPN model mice is antagonized by glycolytic inhibition. While all MPN-driving mutations lead to aberrant JAK2 activation, these mutations often co-exist with mutations in genes that encode epigenetic regulators, including loss of function mutations known to enhance MPN progression. In this perspective we discuss how altered activity of epigenetic regulators (e.g., methylation and acetylation) in MPN-driving stem and progenitor cells may alter cellular metabolism and contribute to the MPN phenotype and progression of disease. Specific metabolic changes associated with epigenetic deregulation may identify patient populations that exhibit specific metabolic vulnerabilities that are absent in normal hematopoietic cells, and thus provide a potential basis for the development of more effective personalized therapeutic approaches.

Highlights

Myeloproliferative neoplasms (MPN) are BCR-ABL-negative hematological malignancies where mutations in hematopoietic stem cells (HSCs) give rise to aberrant production of myeloid clones leading to three distinct clinical phenotypes
MPN-driver mutations enhance Janus kinase 2 (JAK2) signaling which promotes neoplastic hematopoietic stem and progenitor cells (HSPCs) expansion, and altered epigenetic control mechanisms play an etiologic role in the development and progression of MPN
Recent studies provide evidence that altered metabolic control may play an important role in MPN and that altered epigenetic regulation may contribute to neoplastic metabolic profiles

Summary

INTRODUCTION

Myeloproliferative neoplasms (MPN) are BCR-ABL-negative hematological malignancies where mutations in hematopoietic stem cells (HSCs) give rise to aberrant production of myeloid clones leading to three distinct clinical phenotypes. Results from clinical experience suggest targeting JAK2 may not be sufficient or even the best option to reverse the course of disease in MPN patients, and a plethora of pre-clinical studies have suggested a potential benefit of therapeutic combinations Many of these studies have focused on combining JAK2 inhibitors with inhibitors of signaling proteins associated with JAK2 activation with the hope of enhancing the efficacy of JAK2 inhibitor mono-therapy, which could provide therapeutic opportunities for additional patients, as well as potentially overcome JAK2 inhibitor resistance. Concomitant mutation of these genes with MPN driving mutations can enhance disease phenotypes in MPN mouse models [47, 48, 52,53,54,55,56,57] These studies suggest mutations, most often loss of function, of these epigenetic regulators may contribute to disease progression in MPN patients. This suggests HDAC11 may be a therapeutic target to antagonize MPN with minimal adverse effect on normal hematopoiesis [50]

MPN DRIVERS DEREGULATE METABOLIC PROCESSES

Epigenetics and Metabolism in MPN B

Metabolic Control by Histone Deacetylases

Findings

DISCUSSION