Folate metabolism in myelofibrosis: a missing key?

Annals of Hematology https://doi.org/10.1007/s00277-024-06176-y REVIEW Folate metabolism in myelofibrosis: a missing key? Giacomo Maria Cerreto1 · Giulia Pozzi1 · Samuele Cortellazzi1 · Livia Micaela Pasini2 · Orsola Di Martino1 · Prisco Mirandola1 · Cecilia Carubbi1 · Marco Vitale3 · Elena Masselli1,2 Received: 13 November 2024 / Accepted: 28 December 2024 © The Author(s) 2024 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 Myelofibrosis · Myeloproliferative neoplasms · Chronic inflammation · Folic acid · Folate receptor · Onecarbon metabolism Introduction Myelofibrosis is a stem cell-derived clonal hematological malignancy, operationally classified among the classical Philadelphia-negative chronic myeloproliferative neoplasms (MPN). MF is the prototype of onco-inflammatory disorders and consists of two entities: primary MF (PMF) and post-polycythemia vera (PPV)/post-essential Giacomo Maria Cerreto and Giulia Pozzi contributed equally to this work. Marco Vitale Elena Masselli 1 Department of Medicine and Surgery, Anatomy Unit, University of Parma, Via Gramsci 14, Parma 43126, Italy 2 Hematology and BMT Unit, Parma University Hospital (AOUPR), Via Gramsci 14, 43126 Parma, Italy 3 Faculty of Medicine, Vita-Salute University-San Raffaele, Via Olgettina 58, Milan 20132, Italy thrombocythemia (PET) MF, also known as secondary MF (sMF). Perturbation of the JAK/STAT signaling pathway is the hallmark of MF (and MPN in general), which provides a selective advantage to the neoplastic clone over normal hematopoietic stem cells (HSCs) and elicits a myeloproliferative phenotype [1]. Malignant hematopoietic stem/progenitor cells are also the main source of a plethora of pro-inflammatory cytokines, reactive oxygen species, and growth factors capable of perturbing tissue homeostasis at both local (bone marrow, BM) and systemic levels, leading to chronic pro-inflammatory state [2, 3]. In the BM, activated stromal cells produce reticulin and collagen fibers, resulting in bone marrow fibrosis (BMF). Higher degrees of BM fibrosis are associated with a more severe disease stage with a dismal prognosis and a higher risk of leukemic evolution [4]. The chronic pro-inflammatory state and the progressive disruption of BM architecture play a major role in the onset of ineffective erythropoiesis, which underlies MF-related anemia. Prevalence of anemia increases with the duration of the disease: from 35 to 38% at the time of diagnosis, scaling up to 58% within 1 year and 64% beyond 1 year from 13 Annals of Hematology diagnosis, and it has been associated with poor quality of life and reduced overall survival [5]. Current treatments (red blood cell transfusions, erythropoiesis-stimulating agents, androgens, steroids, and immunomodulatory drugs) are associated with multiple side effects and have limited efficacy and durability of response. Encouraging results are emerging from novel therapies, including luspatercept, new-generation JAK-inhibitors (momelotinib, pacritinib), pelabresib (a bromodomain extra-terminal domain inhibitor), imetelstat (a telomerase inhibitor), and navitoclax (a BCL-2/BCL-xL inhibitor) [5, 6]. However, anemia still accounts for one of the most relevant clinical challenges in MF patients. Folate supplementation is often coupled in routine practice with the above-mentioned treatments to tackle ineffective erythropoiesis. Nevertheless, folates have multiple, crucial biological functions as enzyme cofactors involved in nucleotide synthesis during cell proliferation, epigenetic regulation, and redox balance. Folate over-intake may lead to the accumulation of unmetabolized folic acid that has been associated with several chronic inflammatory conditions, including cancer [7]. Folate can modulate the expression of genes encoding for pro-inflammatory and pro-fibrotic cytokines, and, eventually, stimulate cancer cells directly by engaging specific folate receptors. In this review, we will discuss the different aspects of folate metabolism with potential implications in the biology of myeloid malignancies, in particular myelofibrosis. Folate-mediated one-carbon metabolism (FOCM) and its relevance in cancer Folates are water-soluble vitamins sharing a fundamental core structure composed of three chemical moieties: a pteridine ring that can undergo reduction or oxidation, a paraaminobenzoic acid (PABA) linker, and a polyglutamate tail. The pteridine ring and PABA linker bind one-carbon (1 C) units, while the polyglutamate tail anchors the molecule inside the cell [8]. Folates serve as a group of enzyme cofactors that allow the transfer of 1 C units for essential cellular processes, such as purine and pyrimidine biosynthesis, amino acid homeostasis, epigenetic maintenance, and redox defense. They require active systems for cellular uptake. Several genetically distinct and functionally diverse transport systems have been identified: the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), and folate receptors (FR) [9]. RFC is the main transporter for reduced folate uptake in various tissues at physiological pH; whereas PCFT is responsible for intestinal folate absorption in the acidic pH of the upper small intestine. The folate 13 uptake mediated by FR occurs through internalization of the ligand-receptor complex by endocytosis. Once internalized, the endosome fuses with lysosomes to release folates in the cytosol [10]. Alternatively, folate binding to FRs can trigger downstream signaling pathways such as JAK/STAT and ERK1/2 signaling, as described below. The folate metabolism, known as folate-mediated onecarbon metabolism (FOCM), represents a network of interconnected reactions that occur in mitochondria and cytosol, simultaneously [11]. Crucial steps of FOCM are reported in Fig. 1. FOCM is essential for the supply of nucleotides for DNA synthesis and repair, according to the prolifera (...truncated)