Clonal hematopoiesis (CH) occurs when a large fraction of mature blood cells originate from a single hematopoietic stem cell, and is more commonly seen within aging populations. Current evidence suggests somatic mutations in candidate driver genes are responsible for some cases. CH of indeterminate potential, or CHIP, describes CH that co-occurs with a mutation in a leukemia-associated gene at a variant allele frequency of 0.02 or higher, and is associated with an increased risk for myocardial infarction, ischemic stroke, and all-cause mortality.1,2 Recent studies have established an association between CH and hematologic malignancies.3,4

In a review article published in Blood, Julia T. Warren, MD, PhD, and Daniel C. Link, MD, both from the division of hematology-oncology at Washington University School of Medicine in St. Louis, Missouri, summarized current literature investigating the association between CH and hematopoietic malignancy. In addition, they examined aspects of CH associated with leukemic progression.3

CH and Risk for Hematologic Malignancy

CH attributable to point mutations are associated with nearly a 10-fold higher risk of hematopoietic malignancy. While the absolute risk is low, specific elements of CH may result in a greater risk of progression, including the presence of multiple mutations, altered red blood indices, the presence of TP53 or splicesome gene mutations, and a variant allele fraction higher than 10%. Close monitoring is required in the setting of peripheral blood cytopenias as CH confers a high risk of transformation to a myeloid malignancy.3


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Recent evidence suggests that hematopoietic stressors, such as ribosome biogenesis stress and genotoxic stress due to chemotherapy or radiation therapy may also play an important role in the development of CH and evolution to hematopoietic malignancy. Prediction models that include specific elements of CH, in addition to an evaluation of hematopoietic stressors, could help predict and thereby prevent the development of blood malignancies.3

CH and Inherited Bone Marrow Failure Syndromes

Inherited bone marrow failure syndromes (IBMFS) are a group of rare genetic blood disorders characterized by abnormal hematopoiesis and greater risk of developing myeloid malignancies. The pathogenic mechanisms of different IBMFS are variable, and are thought to be related to defects in several biological processes, including ribosome biogenesis, telomere maintenance, and DNA damage repair for Diamond-Blackfan anemia and Shwachman-Diamond syndrome, dyskeratosis congenital, and Fanconi anemia, respectively.Somatic mutations underlying some cases of CH have also been reported in IBMFS; however, the specific mechanisms whereby these mutations drive clonal advantage in each disorder, and their associated leukemic risk are poorly understood.4

Current evidence suggests that surveillance strategies for malignant transformation is dependent upon the ability to prospectively detect specific clones with greater leukemic potential given that CH is not deterministic of malignant progression. Recent studies have described specific frameworks that may help develop clinical surveillance strategies.4

CH-associated Genes

Approximately 20 gene mutations are repeatedly observed in CH, and the effects of these mutations are currently being elucidated at the molecular level in preclinical models. Mutations in epigenetic regulators, such as TET2 and DNMT3A, illicit an advantage by improving self-renewal of hematopoietic cells and preventing differentiation. Recent findings also demonstrate gene mutations involved in the DNA damage response may also improve cell survival.5

Concluding Remarks and Future Perspectives

In an email interview, Margaret A. Goodell, PhD, of Baylor College of Medicine in Houston, Texas, explained that “Monitoring healthy adults starting in their 60s for CH may eventually become common and serve patients. [Similar] to mammograms, or prostate and colon cancer screening, serving as an inexpensive early warning system. Some institutions are [now] establishing ‘CHIP’ clinics to identify and monitor patients with CH.”

She concluded, “I don’t see an immediate impact on [CH effecting] the [specific] type of cancer treatments, but with very early detection, more options may [become] available to patients, and treatments may be initiated much earlier than previously imagined.”

References

  1. Gibson CJ, Steensma DP. New insights from studies of clonal hematopoiesis. Clin Cancer Res. 2018;24(19):4633-4642.
  2. Bowman RL, Busque L, Levine RL. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell. 2018;22(2):157-170.
  3. Warren JT, Link DC. Clonal hematopoiesis and risk for hematologic malignancy. Blood. Published online July 31, 2020. doi:10.1182/blood.2019000991
  4. Tsai FD, Lindsley RC. Clonal hematopoiesis in the inherited bone marrow failure syndromes. Blood. Published online July 31, 2020. doi:10.1182/blood.2019000990
  5. Challen G, Goodell MA. Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood. Published online August 3, 2020. doi:10.1182/blood.2020006510

This article originally appeared on Hematology Advisor