Folate metabolism in myelofibrosis: a missing key?

Abstract

Folates serve as key enzyme cofactors in several biological processes. Folic acid supplementation is a cornerstone practice but may have a "dark side". Indeed, the accumulation of circulating unmetabolized folic acid (UMFA) has been associated with various chronic inflammatory conditions, including cancer. Additionally, by engaging specific folate receptors, folates can directly stimulate cancer cells and modulate the expression of genes coding for pro-inflammatory and pro-fibrotic cytokines.This evidence could be extremely relevant for myelofibrosis (MF), a chronic myeloproliferative neoplasm typified by the unique combination of clonal proliferation, chronic inflammation, and progressive bone marrow fibrosis. Folate supplementation is frequently associated with conventional or investigational drugs in the treatment of MF-related anemia to tackle ineffective erythropoiesis. In this review, we cover the different aspects of folate metabolism entailed in the behavior and function of normal and malignant hematopoietic cells and discuss the potential implications on the biology of myelofibrosis.

Keywords: Chronic inflammation; Folate receptor; Folic acid; Myelofibrosis; Myeloproliferative neoplasms; One-carbon metabolism.

Fig. 1

Overview of Folate-mediated One-Carbon Metabolism (FOCM) and crucial steps targeted by anti-cancer drugs. Once internalized by FR and RCF, folic acid (FA) goes through a series of redox enzymatic reactions within cells, known as FOCM. These reactions involve the subsequential conversion of 1 C units into various oxidation states by both cytosolic (SHMT1 and MTHFD1) and mitochondrial (SHMT2 and MTHFD2) enzymes. The products of FOCM, including 10-formyl-THF, 5,10-methylene-THF and 5-methyl-THF are crucial for DNA and purine synthesis, as well as methylation reactions. 5-methylTHF enters the cell through RFC and serves as a substrate for the MTR and vitamin B12-mediated re-methylation of homocysteine to methionine. This reaction also produces THF, replenishing the starting substrate of FOCM. Excessive FA can overwhelm the internalization capacity of folate transporter systems leading to increased levels of circulating UMFA. Created in BioRender (BioRender.com/w80m96). Abbreviations: FR, folate receptor; RFC, reduced folate carrier; FA, folic acid, UMFA, unmetabolized folate; FOCM, folate-mediated one-carbon metabolism; DHF, dihydrofolate; DHFR, dihydrofolate reductase; THF, tetrahydrofolate; SHMT1/2, serine hydroxymethyltransferase 1/2; MTHFD 1/2 methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1/2; MTHFR, methylene tetrahydrofolate reductase; 5-FU, 5-fluoruracil, dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate, TYMS, thymidylate synthase; MTR, methionine synthase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine

Fig. 2

Exploring the potential mechanisms of how folate can affect MF. FA can interact with/enter immune cells expressing FR or RCF. In immune cells it can activate: (i) both pro-inflammatory and anti-inflammatory gene expression programs; (ii) pro-proliferative signals via JAK/STAT3 and ERK1/2 pathways; (iii) M2/TAM-induced fibroblast differentiation in myofibroblasts. All these events may contribute to clonal expansion and bone marrow fibrosis. FA might promote the fitness of the malignant clone directly in case of expression of FR on MF CD34 + cells. Fibrosis can also be promoted by excess folate intake, leading to circulating UMFA. Created in BioRender (BioRender.com/w80m97)