Implications for metabolic disturbances in myelodysplastic syndromes

Abstract

The Myelodysplastic Syndromes (MDS) are heterogeneous stem cell malignancies clinically characterized by bone marrow dysplasia, peripheral blood cytopenias, and a high risk for transformation to acute myeloid leukemia. In early stages of disease, differentiation defects and maturation blocks result in deficient hematopoiesis. In higher risk disease, unrestricted proliferation of immature blast cells leads to leukemogenesis. Disease pathogenesis can be attributed to many factors including chronic inflammation that is driven in part by commonly found somatic gene mutations (SGM) fostering expansion of malignant clones while suppressing normal hematopoiesis. Cellular metabolism that both directly and indirectly regulates hematopoietic stem cell (HSC) fate, is intimately connected to the immune system, is altered by MDS somatic gene mutations and is likely is a major contributor to disease pathophysiology. Despite this likely role in pathobiology, there is an underwhelming depth of literature on the subject and the precise metabolic dysregulations in these myeloid malignancies have yet to be fully delineated. In this review, we will provide a general overview of several major metabolic processes and how each directs HSC fate, provide a summary of metabolic studies in MDS, discuss how common SGM and inflammation influence metabolic pathways to drive bone marrow failure, and end with a discussion of standards of care and how these should be carefully considered in the context of metabolic dysregulation.

Keywords: Glycolysis; Inflammation; Metabolism; Mitochondria; Somatic Gene Mutation.