Quantifying the Incidence of Clonal Hematopoiesis in Human Conditions of Increased Inflammation
Dr. Grant Challen and Christine R. Zhang
Genetic mutations characteristic of blood cancers can be detected in the blood of almost all healthy individuals over age 50. This phenomenon is known as clonal hematopoiesis (CH), and while the presence of such mutations does increase the risk of blood cancer development, it does not predestine an individual for leukemia. A major unresolved question is what factors promote the expansion of mutant clones in certain people, and can these mechanisms be exploited to prevent disease progression? The goal of this work is to determine the mechanisms by which inflammatory signals promote the expansion of pre-malignant HSC clones, which could provide a rationale for the development of specific intervening strategies for individuals who may be more “at-risk”
To determine if inflammation influences CHIP clones, Dr. Challen’s team sequenced peripheral blood cells from patients with ulcerative colitis (UC), an autoimmune disease with higher serum levels of pro-inflammatory cytokines. They prepared Haloplex libraries from genomic DNA from 190 UC patients and sequenced them on an Illumina NovaSeq using the MyeloSEQ platform at GTAC@MGI. Data analysis identified 234 unique variants across 121 patients. Using the traditional cutoff of VAF >0.02, their data showed the incidence of CHIP is approximately doubled in UC patients compared to the general population. The most recurrently mutated genes were DNMT3A and PPM1D, while TET2 mutations seem to be negatively selected in this patient population. These data support their hypothesis that inflammatory signals may provide selective pressure for the expansion of mutant clones in the bone marrow. Parallel studies with genetic mouse models are investigating the mechanisms and a thorough examination of the mechanisms will be the next step. The long-term goal of this work is to develop strategies to eliminate or selectively inhibit emerging mutant HSC clones as a mechanism of cancer prevention.
For continued educational resources by this team, read the publication:
Zhang CRC, Nix D, Gregory M, Ciorba MA, Ostrander EL, Newberry RD, Spencer DH, Challen GA. Inflammatory cytokines promote clonal hematopoiesis with specific mutations in ulcerative colitis patients. Exp Hematol. 2019 Dec;80:36-41.PubMed PMID: 31812712; PubMed Central PMCID: PMC7031927.