Abstract
Self-renewal and function of hematopoietic stem cells arose as possible drivers in genetic studies.
Major Finding: Self-renewal and function of hematopoietic stem cells arose as possible drivers in genetic studies.
Approach: Risk loci were identified using genome-wide association studies and whole-genome sequencing.
Impact: These findings suggest how clonal hematopoiesis and resulting myeloproliferative neoplasms develop.
Cases of clonal hematopoiesis of indeterminate potential (CHIP), a condition in which mutant clones of hematopoietic stem cells (HSC) accumulate, are common with aging and can take a relatively benign course or progress to become myeloproliferative neoplasms (MPN) and, in some cases, leukemia. Recent work has shown that CHIP is a risk factor for coronary artery disease and myocardial infarction as well. Complementary studies by Bick, Weinstock, and colleagues and Bao, Nandakumar, Liao, and colleagues identified genetic factors and biological mechanisms underlying the heritability of CHIP and MPNs. Bick, Weinstock, and colleagues performed germ- and somatic-cell whole-genome sequencing of 97,691 people, identifying 4,229 participants with CHIP, whereas Bao, Nandakumar, Liao, and colleagues performed a genome-wide association study including 3,797 people with known MPNs and 1,152,977 control participants. Bick, Weinstock, and colleagues found germline mutations within the TERT locus, a locus at an intergenic region spanning KPNA4 and TRIM59, and a locus near TET2 (which encodes an enzyme that initiates the epigenetically important cytosine demethylation process); the latter two loci had not previously been found in association with CHIP. In vitro and in silico analyses revealed that the risk variant at the locus near TET2 disrupted a distal enhancer of TET2, downregulating TET2 and promoting HSC self-renewal. Bao, Nandakumar, Liao, and colleagues identified 17 MPN risk loci (including one in TET2), seven of which were previously unknown. An examination of blood-cell traits of 408,241 individuals showed that MPN risk was positively correlated with high counts of many cell types derived from hematopoietic stem and progenitor cells. Additionally, highly risk-associated variants were associated with open, active chromatin in HSCs, and longer telomere length in leukocytes was correlated with higher MPN risk. Together, these results from Bao, Nandakumar, Liao, and colleagues imply that HSC function and self-renewal characteristics are associated with MPN risk. Therefore, the work of both Bick, Weinstock, and colleagues and Bao, Nandakumar, Liao, and colleagues implicates HSC self-renewal as a key driver of clonal hematopoiesis and the resulting MPNs, and the combination of these two efforts has uncovered numerous previously unknown MPN risk loci that are worth investigating further.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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