Abstract
Simple SummaryThe genome is stored in the limited space of the nucleus in a highly condensed form. The regulation of this packaging contributes to determining the accessibility of genes and is important for cell function. Genes affecting the genome’s packaging are frequently mutated in bone marrow cells that give rise to the different types of blood cells. Here, we first discuss the molecular functions of these genes and their role in blood generation under healthy conditions. Then, we describe how their mutations relate to a subset of diseases including blood cancers. Finally, we provide an overview of the current efforts of using and developing drugs targeting these and related genes.Mutations in genes encoding chromatin regulators are early events contributing to developing asymptomatic clonal hematopoiesis of indeterminate potential and its frequent progression to myeloid diseases with increasing severity. We focus on the subset of myeloid diseases encompassing myelodysplastic syndromes and their transformation to secondary acute myeloid leukemia. We introduce the major concepts of chromatin regulation that provide the basis of epigenetic regulation. In greater detail, we discuss those chromatin regulators that are frequently mutated in myelodysplastic syndromes. We discuss their role in the epigenetic regulation of normal hematopoiesis and the consequence of their mutation. Finally, we provide an update on the drugs interfering with chromatin regulation approved or in development for myelodysplastic syndromes and acute myeloid leukemia.
Highlights
Myelodysplastic syndromes (MDS) are part of a spectrum of clonal myeloid diseases starting with the asymptomatic expansion of mutated hematopoietic stem cell (HSC) clones and frequently ending with transformation to full-blown secondary acute myeloid leukemia [1]
The azanucleosides, 5-azacitidine, and 5-aza-2 -deoxycytidine are nucleoside analogs that have become the mainstay of MDS treatment for intermediateto high-risk MDS patients, who are ineligible for allogeneic hematopoietic stem cell transplantation (HSCT)
clonal hematopoiesis of indeterminate potential (CHIP), MDS and secondary acute myeloid leukemia (sAML) are intimately linked to epigenetics through mutations affecting chromatin regulators and alterations in chromatin structure and its modifications
Summary
Myelodysplastic syndromes (MDS) are part of a spectrum of clonal myeloid diseases starting with the asymptomatic expansion of mutated hematopoietic stem cell (HSC) clones and frequently ending with transformation to full-blown secondary acute myeloid leukemia (sAML) [1]. The evolution and progression of MDS and sAML is intimately linked to changes in the regulation of chromatin function and epigenetics. Epigenetic abnormalities co-occur with genetic and cytogenetic changes in MDS and sAML, and together, contribute to the full manifestation of the disease [4]. We provide a short background on MDS and sAML as part of a spectrum of clonal myeloid diseases with increasing severity. After a brief introduction of the concept of epigenetics and its relation with chromatin modifications, we discuss those epigenetic regulators that are affected by mutations in MDS and sAML. Epigenetic alterations contribute to other hematologic diseases, and we would like to refer to recent reviews discussing these aspects in lymphoma [6] and other types of AML not related to MDS [7]
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