The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

Abstract

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated hematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal hematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic hematopoietic differentiation, and the absence of features that define acute leukemia. Over 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation, and transcription. In this review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems, and therapeutic approaches.

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

“…Together, these studies Recurrently mutated genes are classified into functional categories. Mutational frequency data are derived from the following resources: CHIP [11][12][13], MDS [2], AML [35,71], and AA [17,18] suggest that a significant proportion of AA patients with no morphological evidence of MDS possess mutations in myeloid cancer-related genes including epigenetic regulators, indicating functional relevance of epigenetic modifiers in clonal hematopoiesis in AA. In the following chapter, we will review pleiotropic effect of major epigenetic modifiers in HSC regulation and leukemogenesis, mutations of which were reported in individuals with clonal hematopoiesis.…”

“…This phenomenon has been termed clonal hematopoiesis of indeterminate potential (CHIP), which is associated with increased risk of developing hematologic malignancy and decreased overall survival [1,2]. The most frequently mutated genes found in individuals with CHIP were epigenetic modifiers, including DNA methyltransferase 3A (DNMT3A), Ten-eleven-translocation 2 (TET2), and Additional sex combs-like 1 (ASXL1).…”

Prevalent premalignancy

“…5 Finally, the production of reactive oxygen species (ROS), for example, induced by cytotoxic drugs such as etoposide, doxorubicin, or cytarabine, determines nuclear localization and activation of BACH2, necessary for the drug-induced cell death. 8 Now, Zhang and colleagues have given BACH2 a breath of fresh air (more specifically, oxygen), studying its role in MCL, but their results also highlight the complexity of the mechanism controlling BACH2 activity, a topic certainly requiring further work. Do the findings in MCL apply to other lymphomas or leukemias as well?…”

“…Mutations in MTA2 have previously been found in preleukemic HSCs, and many other epigenetic regulators are recurrently mutated in CHIP. 8,11 Further work will be needed to confirm whether mutations in MTA2 can, in fact, lead to clonal hematopoiesis and whether there are additional genes that lead to clonal expansion and hematologic malignancy when mutated. These 2 reports provide evidence of familial predisposition to clonal hematopoiesis.…”

“…[5][6][7] Together, these findings have led to a model in which HSCs acquire mutations over time leading to clonal expansion and eventually to overt malignancy. 8 Most somatic mutations are biologically silent passenger events that create a mutational signature marking each HSC and its progeny. 9 The presence of a detectable collection of somatic mutations within the blood is therefore suggestive of clonal expansion from a single HSC.…”