Somatic mutations in bone marrow or peripheral blood driving clonal expansion of hematopoietic stem and progenitor cells continue to draw tremendous scientific and clinical interest. With the expansion of large-scale genomic sequencing strategies, clonal hematopoiesis (CH) is rapidly evolving into a potential paradigm that connects aging, inflammation, and human health. As CH is almost ubiquitous with age but biologically and phenotypically heterogeneous, much work remains to be done to fully understand its clinical repercussions. This year’s meeting includes several remarkable studies that help “move the needle” in the field.
A potentially clinically relevant study, “Platelet-Restricted Clonal Hematopoiesis” (to be presented tomorrow by Nikolaos Sousos, MD) introduces the novel concept of platelet-restricted CH and demonstrates that somatic events among genes commonly involved in CH can be detected through genomic sequencing of platelet DNA in individuals without hematologic abnormalities. This study challenges previous analyses focusing on whole-blood or granulocyte-specific DNA sequencing, showing that platelet-specific DNA sequencing enhances the ability to detect potentially relevant clones (those with an allele frequency >2%). Could platelet-specific DNA become relevant to explain non-malignant vascular complications associated with CH?
As hematologists, we are familiar with the risks of somatic clonality, yet how our germline genetic backgrounds influence the risk of CH — as well as the downstream health consequences — is a relevant question that remains greatly unexplored.
A must-see presentation in the session Clonal Hematopoiesis, Aging and Inflammation: From Omics to Discoveries (Monday, 2:45 p.m. – 4:15 p.m., Convention Center, Room 24) is “Genetic Determinants of Clonal Hematopoiesis and Progression to Hematologic Malignancies in 479,117 Individuals.” This work, to be presented by Jie Liu, MBBS, demonstrates that several pathogenic germline variants in genes predisposing to CH act through cellular pathways that increase mutational tolerance or select for somatic mutated clones. This collaborative effort from the U.K. Biobank, the MSKCC IMPACT study, and the Cancer Genome Atlas also identified a synergistic effect between germline and somatic alterations that enhances the risk of hematologic malignancies in CH carriers, implying that patient-specific models accounting for genetic background are needed to accurately predict an individual’s risk of cancer. Is this true for other health outcomes associated with CH? Could germline testing aid in the difficult task of estimating risk and counseling people with CH? Further building on these data, in the same session, Sean Wen, PhD, will present “Ancestry-Specific Genetic Determinants of Clonal Haematopoiesis: A Comparative Analysis of 136,401 Admixed Americans and 419,228 Europeans.” This work revealed that CH prevalence determined using whole-exome sequencing was lower in the Mexico City Prospective Study cohort (Americans) than in age-matched individuals from the U.K. Biobank (European). Intra-population analysis of Americans identified that higher European ancestry fraction was associated with increased prevalence of some but not all somatic mutations, suggesting ancestry-specific genetic associations.
Perhaps the most important questions that have emerged in the field of CH are related to management. Can we prevent these clones from evolving into hematologic malignancies? Can we target any of the several deleterious health outcomes linked to this condition?
As we await results from ongoing clinical studies, preclinical data continue to build arguments for potential strategies targeting CH. Tomorrow’s session on Clonal Hematopoiesis, Aging and Inflammation: Translational Innovations (4:30 p.m. – 6:00 p.m., Convention Center, Room 24) will include coverage of “Mechanisms and Therapeutic Strategies to Reverse TET2 Mutant Clonal Haematopoiesis and the Risk of MDS, AML, and Atherosclerotic Cardiovascular Disease.” In this work, Nicole Prutsch, PhD, explored whether selectively suppressing the growth of mutant clones in the bone marrow can reduce adverse outcomes in vivo. The study tested eltanexor, a nuclear export inhibitor that selectively targets TET2-mutant hematopoietic stem cells, in a murine model of CH. Treatment was associated with decreased number of circulating mutant granulocytes and degree of aortic atherosclerotic plaque formation. Similarly, in “Chronic TNF in the Aging Microenvironment Exacerbates TET2-loss-of-Function Myeloid Expansion,” Candice Quin, PhD, used a murine model to demonstrate that age-associated increases in TNF signaling are important for TET2-mutant myeloid expansion and inflammatory responses. The study also showed that treatment with adalimumab, an anti-TNF agent, reduced clonal burden in a small cohort of human subjects with baseline CH. Both these abstracts build on preclinical evidence that will hopefully help design interventional studies by targeting the mutated clones themselves or the inflammatory responses triggered by clonal myeloid expansion, thought to be the main mechanism of end-organ damage. Could eltanexor or TNF blockade help drive the future of our crusade against CH?
The clock is ticking, and as we (and our hematopoietic stem cells) grow older, we are also growing wiser. The #ASH23 sessions on CH illustrate how we are continually adding to our knowledge surrounding CH identification and stratification, while highlighting the pressing need to develop therapeutic approaches. As more individuals undergo genomic sequencing, hematologists will inevitably be called upon to evaluate and treat this growing population.
Dr. Adrianzen Herrera indicated no relevant conflicts of interest.
