Clonal Hematopoiesis: Impact on Health and Disease

Abstract

The expansion of hematopoietic cell clones, carrying alterations in genes frequently mutated in hematologic malignancies, in the absence of altered hematopoietic cell counts or otherwise defined disease criteria, is termed clonal hematopoiesis (CH). CH is frequently detectable in aged individuals and associates with numerous detrimental health impacts. These impacts are highly dependent on the type of mutations and the cellular context in which they manifest. Mutations in the hematopoietic stem and progenitor cell (HSPC) compartment as well as in self-renewing more mature cells associate with increased risks of malignant disease, while mutations penetrating via hematopoiesis in non-self-renewing, mature cells associate with altered immune functions and consequent systemic effects, which can initiate or aggravate multiple non-malignant diseases. Here we review the definitions of CH, major genetic drivers and lineage penetrance, and we highlight how CH impacts on hematological and non-hematological conditions.

Keywords: clonal hematopoiesis; health outcomes; leukemia.

FIGURE 1

Age associates with key properties of clonal hematopoiesis (CH). (A) The estimated prevalence of CH as a function of age varies according to the variant allele frequency (VAF) used as a threshold for CH definition, which in turn depends on the sequencing method used. (B) Representative depiction of the average clonal size as a function of age (solid gray line), indicating increased clonal sizes in advanced ages. Mutation‐specific clonal expansions are indicated (dashed lines), with DNMT3A‐mutant clones showing higher expansion rates in earlier stages, TET2‐mutant clones showing a later onset and then a constant life‐long expansion rate, and spliceosome gene‐mutated clones showing a late onset and the highest expansion rates [7]. The category of spliceosome mutations includes SF3B1, SRSF2 and U2AF1. (C) Representative depiction of the prevalence of mutational number per individual according to age category, indicating increased mutational number in advanced ages (graph adapted from published data [8]). (D) Representative depiction of the proportion of mutations in different driver genes among all mutations detected per age category, indicating reduced relative frequency of DNMT3A mutations and increases in TET2 and ASLX1 mutations in advanced age. The category of spliceosome mutations includes SF3B1, SRSF2 and U2AF1 (graph adapted from published data [8]).

FIGURE 2

Health impacts of CHIP. Schematic depiction of the cellular compartment affected by CHIP‐associated mutations (left), the reported functional cellular alterations that associate with cell‐type specific CHIP mutations (middle) and the reported health impacts associated with CHIP (right). Red arrows between middle and right box indicate association but not causality. CAR, chimeric antigen receptor; CKD, chronic kidney disease; CLD, chronic liver disease; COPD, chronic obstructive pulmonary disease; CRS, cytokine release syndrome; HSC, hematopoietic stem and progenitor cell; ICANS, immune effector cell‐associated neurotoxicity syndrome; iCDV, ischemic cardiovascular disease; LC, lung cancer; OR, odds ratio; VTE, venous thromboembolism.

FIGURE 3

Cell of origin in clonal conditions of the hematopoietic system. Schematic depiction of the implications of the cell of origin in hematopoietic clonal conditions. In CH (CHIP and CCUS) (left panel), the mutations are thought to occur at the HSC level leading to higher variant allele frequency detection in the mature myeloid compartment, with minor presence of the mutation in the lymphoid compartment. In lymphoid clonal conditions (right panel), the mutations can occur in one of three scenarios: (A) Mutation occurrence in the HSC compartment with transmission to lymphoid (and presumably to myeloid) progeny, which will then undergo receptor rearrangement to form a T/B cell receptor‐diverse mutant clone. How L‐CHIP mutations propagate in the myeloid lineage is currently largely unknown (depicted with question mark). (B) Mutation occurrence in the lymphoid progenitor compartment before receptor rearrangement, leading to a T/B cell receptor‐diverse mutant clone. (C) Mutation occurrence at lymphocyte developmental stages, which have already undergone T‐ or B‐cell receptor rearrangement, which upon expansion form a monoclonal T‐ or B‐cell receptor mutant clone. The distribution of mutations in other lineages (e.g., natural killer cells) has been omitted for simplicity. MBL, monoclonal B lymphocytosis; T‐CUS, T‐cell clones of uncertain significance; VAF, variant allele frequency.