Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms

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.

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

“…Numerous biological derangements are associated with the previously described mutations commonly detected in MPNs. The subsequent metabolic alterations are closely linked to mitochondrial biogenesis and include modifications in apoptosis, glycolysis, fatty acid metabolism, glutaminolysis, and subsequently in OXPHOS [356][357][358]. Ligand independent activation of the JAK/STAT pathway is a common oncogenic modality amongst MPNs.…”

“…The enhanced activity of 6-phosphofructo-1-kinase depends on 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which is controlled by the JAK2V617F kinase. These metabolic changes enhance energy production through glycolysis and the subsequent shunting into OXPHOS within the mitochondria [358]. Not only are the metabolic processes of the neoplastic cells altered, but they also induce changes in neighboring cells by inducing stromal cells to release amino acids, lipids, and other molecules that can be used for energy production.…”

Overview of dyslipidemia and metabolic syndrome in myeloproliferative neoplasms

“…Some studies have demonstrated that carriers of JAK2 gene mutations show increased insulin, hypoglycemia, and adipose tissue atrophy, reinforcing the link between this mutation and metabolic disorders[ 56 ]. Currently, there is growing evidence that JAK2 gene mutations can lead to altered lipid metabolism due to increased metabolic demand[ 57 , 58 ].…”

Current Approaches to Epigenetic Therapy

“…As for LMW combination with conventional therapy, the striking example is the use of Chidamide [15], which is being studied in seven clinical trials in the III and IV phases. The next example is the use of O 6 -benzylguanine, an O 6 -alkylguanine-DNA alkyltransferase (AGT) inhibitor, in combination with standard therapy, which slows down the progression of glioblastoma and gliosarcoma in comparison with temozolomide treatment [16]. As for azacitidine, a single cohort study by Ruan and colleagues first demonstrated that the oral form of azacitidine in combination with the CHOP regimen (Cyclophosphamide, Doxorubicin, Oncovin and Prednisolone) showed good effectiveness [17].…”

“…This process depends on the balance of enzymes that catalyze reversible modifications of histones and DNA molecules [ 1 ]. Disruption of this balance may trigger the development of various diseases [ 2 , 3 , 4 , 5 , 6 ]. Currently, new approaches to correcting epigenetic mistakes are being actively developed due to progress in molecular biology methods.…”