Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies

Abstract

Clonal hematopoiesis (CH) broadly describes the expansion of a clonal population of blood cells with one or more somatic mutations. Individuals with CH are at greater risk for hematological malignancies, cardiovascular disease, and increased mortality from non-hematological cancers. Understanding the causes of CH and how these mutant cells interact with cells of other tissues will provide critical insights into preleukemic development, stem cell biology, host-immune interactions, and cancer evolution. Here we discuss the clinical manifestations of CH, mechanisms contributing to its development, the role of CH in clonal evolution toward leukemia, and the contribution of CH to non-hematological disease states.

Figure 1. Clonal Hematopoiesis in Relation to Selective Pressures and Secondary Hematological Disease

Highlighted in orange are potential sources of mutagenic stress that can generate somatic variation in CH, and these include aging-associated mutagenesis, chemotherapy-induced somatic variation, and exposure to exogenous genotoxic stresses, including smoking. Chemotherapy and aging also serve as selective pressures (indicated by double-headed arrows) whereby somatic variants may be selected for if they have better fitness. These selective pressures can lead to clonal outgrowth (as depicted in Figure 2) and the development of CH. Somatic variants can also lead directly to de novo AML or MDS formation. CH can be followed by the development of cytopenias as evident in CCUS, with additional dysplasia resulting in MDS. AML development as a result of CH can arise from an MDS intermediate, but can also likely bypass this progression. CH, clonal hematopoiesis; CCUS, clonal cytopenias of undetermined significance; MDS, myelodysplatic syndrome; AML, acute myeloid leukemia.

Figure 2. Clonal Expansion under Selective Pressure

(A) Schematic depicting clonal evolution under negative selection with a deleterious event, no somatic variation, neutral selection, and positive selection with an advantageous event. (B–D) Depiction of selective pressures: (B), aging; (C), chemotherapy; and (D), immune-mediated pressure. Clonal outgrowth is represented with time on the×axis and relative abundance of HSC clones on the y axis. The dashed line indicates the duration of time that the selective pressure is present. The color of the dot indicates the somatic variants as indicated. (E) Stochastic drift is shown with the outgrowth of a single HSC clone yielding somatically distinct neutral daughter cells indicated by differing shades of blue. The bar plot on the right indicates abundance of HSCs following stochastic drift for each clone following three generations of HSC division.

Figure 3. Epigenetic Regulators of Clonal Hematopoiesis

Schematic of DNMT3A catalyzing CpG methylation (black circles), TET2 generating 5hmC (blue circles), and ASXL1 generating H3K27 trimethylation (red circles) by recruiting the PRC2 complex member EZH2. Associations with loss of function and hematological disease are listed to the right. Findings supported by mouse and human data are denoted with an “m” and “h,” respectively.

Figure 4. CH-Associated TET2 Mutations and Interaction with Nonhematologic Disease

Schematic of TET2-dependent repression of IL-6 and IL-1beta by recruitment of HDAC proteins. TET2 loss of function leads to de-repression of Il6 and Il1b cytokine expression. This deregulation has impacts on atherosclerotic plaque formation, inflammation resolution, and the tumor microenvironment. Age-related myeloid skewing and mutation-dependent lymphoid department skewing alters the tumor microenvironment immune landscape.