Myelodysplasia Syndrome, Clonal Hematopoiesis and Cardiovascular Disease

Abstract

The development of myelodysplasia syndromes (MDS) is multiphasic and can be driven by a plethora of genetic mutations and/or abnormalities. MDS is characterized by a hematopoietic differentiation block, evidenced by increased immature hematopoietic cells, termed blast cells and decreased mature circulating leukocytes in at least one lineage (i.e., cytopenia). Clonal hematopoiesis of indeterminate potential (CHIP) is a recently described phenomenon preceding MDS development that is driven by somatic mutations in hemopoietic stem cells (HSCs). These mutant HSCs have a competitive advantage over healthy cells, resulting in an expansion of these clonal mutated leukocytes. In this review, we discuss the multiphasic development of MDS, the common mutations found in both MDS and CHIP, how a loss-of-function in these CHIP-related genes can alter HSC function and leukocyte development and the potential disease outcomes that can occur with dysfunctional HSCs. In particular, we discuss the novel connections between MDS development and cardiovascular disease.

Keywords: ASXL1; DNMT3A; JAK2; P53; TET2; cardiovascular disease; clonal hematopoiesis and indeterminate potential (CHIP); hematopoietic stem cell (HSC); myelodysplasia syndrome.

Figure 1

Transformations from normal hematopoiesis to acute myeloid leukemia (AML) development. (A) Normal: Normal hematopoiesis is highly regulated, whereby hematopoietic stem cells (HSCs) can self-renew and differentiate into progenitor cells. Progenitor cells differentiate into immature blood cells (blast cells) and then into mature white blood cells (WBCs). (B) Pre-MDS (myelodysplasia syndrome): Clonal hematopoiesis of indeterminate potential (CHIP) occurs when a HSC acquires a somatic mutation resulting in a proliferative advantage; giving rise to a mutated clone. While the levels of WBCs do not change, there are mutated clonal WBCs detected in the blood. Clonal cytopenia of undetermined significance (CCUS) presents with CHIP, as well as with cytopenia. (C) MDS: The development of significant bone marrow (BM) blast cells, BM dysplasia and cytopenia is usually associated with at least 1 genetic abnormality (either a gene mutation or chromosomal defect). MDS is considered low risk (transformation potential) when blast cell numbers are relatively low, and high risk when BM dysplasia is advanced. (D) AML: A leukemic transformation occurs that results in excessive BM expansion, BM dysplasia and pathological WBC production.

Figure 2

Hematopoietic and disease consequences of the top 5 genes mutated in CHIP. (A) DNMT3A: KO, single spot loss-of-function mutation and CRISPR editing studies [14,36,60,67,68,70,78]. (B) TET2: KO, CRISPR editing or mutation in the catalytic domain only studies [13,14,17,20,68,78,79]. (C) P53: studies utilizing P53 loss-of-function mutations [80,81,82,83,84,85,86]. (D) ASXL1: studies utilizing loss-of-function mutations [14,87,88,89,90,91]. (E) JAK2: studies reporting the V617F mutation [14,86,92,93]. KO, Knock Out; HSC, hematopoietic stem cell.