Study Identifies Key Mutations That Promote Stem Cell Growth and Increase Leukemia Risk

In a report published in Nature, researchers linked three genetic loci to the increased proliferation of hematopoietic stem cells (HSCs), which may subsequently increase the risk of clonal hematopoiesis of indeterminate potential (CHIP) and malignancies. This included a variant in a non-coding region near TET2 that was specific to people of African descent.

“Using genetics, we may be able to better identify who’s at increased risk of developing CHIP and leukemia or other diseases,” lead study author Alexander Bick, MD, PhD, of Vanderbilt University Medical Center, told ASH Clinical News. “If we’re better able to identify who’s at increased risk, that may help us target who to screen more closely for these diseases, catch it early, or try to identify treatments during the early stages of disease.”

The researchers analyzed genetic and health data from 97,691 people collected through the National Heart, Lung, and Blood Institute’s (NHLBI’s) Trans-Omics for Precision Medicine (TOPMed) program. Dr. Bick and colleagues identified 4,229 people with CHIP in TOPMed.

Another distinct set of whole-genome sequencing samples from the TOPMed Freeze 8 release also were identified to replicate the findings from the TET2 genetic association analysis (n=9,389).

TOPMed is a diverse cohort, the authors noted. Approximately 58% of people in the program are of non-European ancestry and approximately 82% are U.S. residents with diverse ancestry and ethnicity, including:

  • European (40%)
  • African (32%)
  • Hispanic or Latino (16%)
  • Asian (10%)

The genetic analysis revealed several germline genetic mutations that gave rise to clonal hematopoiesis, which occurred principally through two pathways. “The first pathway is related to genome integrity,” said Dr. Bick, “or how likely one is to get a mutation.” TERT was the top signal, followed by CHEK2, which is involved in DNA damage repair.

In their cohort analysis, the investigators found a region of the genome associated with CHIP in only people with African ancestry: the noncoding variant at the TET2 locus. This variant was specific to donors with African ancestry and is known to disrupt the HSC TET2 enhancer, resulting in decreased TET2 expression and higher levels of self-renewal of HSCs, the authors explained.

They also observed lower-than-normal levels of TET2 mRNA in blood samples from 16 African Americans in the cohort who had 1 copy of this genetic variant.

To confirm these findings in the lab, researchers removed the TET2 gene from mice and found subsequent increased self-renewal of HSCs, resulting in more stem cells. Cell colonies also grew more rapidly when the investigators “turned down” expression of TET2 in isolated human HSCs.

“Using genetics, we may be able to better identify who’s at increased risk of developing CHIP and leukemia or other diseases.”

—Alexander Bick, MD, PhD

Dr. Bick added that the genetic predisposition to clonal hematopoiesis and myeloproliferative neoplasms (MPNs) was almost identical, suggesting that people who are born with this increased risk of CHIP are also at an increased risk of MPNs.

The researchers found “very specific” signatures of increased inflammation, according to Dr. Bick, including interleukin 6 (IL-6) and IL-1 beta.

“We think the mutation is driving the inflammation, but there’s also an active area of research trying to understand whether people who have increased inflammation are at increased risk of developing this and other blood disorders,” he said. “An active future direction of investigation is to try to understand how inflammation is feeding into clonal hematopoiesis and causing it to evolve into MPNs and myeloid leukemia.”

Limitations of this study included the reduced sensitivity for the detection of CHIP with low allele fractions, as well as the cross-sectional nature of the analyses of CHIP with non-genetic risk factors and biomarkers.

Study authors report no relevant conflicts of interest.


Bick AG, Weinstock JS, Nandakumar SK, et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature. 2020;586:763-768.