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


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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