Experts discuss insights from latest research into clonal hematopoiesis

Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-associated condition in individuals who do not have a hematologic malignancy or altered blood counts. It is defined by the presence of clonal, somatic mutations that are commonly the initiating events for myeloid malignancies, and it is associated with a strikingly increased risk of hematologic malignancy.

Benjamin L. Ebert, MD, PhD
Benjamin L. Ebert, MD, PhD

“Clonal hematopoiesis is an incredibly fast-moving field with major clinical implications,” said Benjamin L. Ebert, MD, PhD, who chaired the Annual Meeting symposium Clonal Hematopoiesis on Monday, April 17.

During the session, which can be viewed on the virtual meeting platform by registered Annual Meeting participants through July 19, 2023, Ebert and two other experts discussed how clonal hematopoiesis is revealing insights into the initiation of hematologic malignancies, the biology of clonal selection, and the broad consequences of somatic mutations on the function of terminally differentiated blood cells. Clonal hematopoiesis (CH) is a broad umbrella that encompasses CHIP, clonal cytopenia of uncertain significance (CCUS), myeloid cancers, lymphoid CH, micro-CH, and CH with unknown driver.

Only a minority of individuals with CHIP develop myeloid malignancies, but large cohort studies have found that CHIP is associated with an increased risk for a range of inflammatory diseases, as well as the development of solid tumors, explained Ebert, the George P. Canellos, MD, and Jean S. Canellos Professor of Medicine at Harvard Medical School and Chair of Medical Oncology at the Dana-Farber Cancer Institute.

Individuals with CHIP also have increased overall mortality and increased risk of cardiovascular disease, including heart failure, atherosclerosis, and atrial fibrillation, Ebert said. CHIP is also associated with a two-fold increased risk of prevalent or incident chronic liver disease.

Multiple prognostic factors have been combined to produce a clonal hematopoiesis risk score (CHRS), Ebert noted. CHRS defines three distinct risk groups. About 90 percent of those with CHIP/CCUS are at low risk, with a 10-year survival of 93.7 percent versus 95.8 percent for matched cohorts with no CHIP/CCUS. Ten-year survival for the intermediate risk group is about 84 percent, and 51.2 percent for the high-risk group.

“These are the people we need to see in the clinic,” Ebert said. “We have no specific clinical intervention yet, but we can and should focus on prevention and follow-up.”

Siddhartha Jaiswal, MD, PhD
Siddhartha Jaiswal, MD, PhD

Ebert noted that an unplanned analysis from a large clinical trial found that Tet2-mutant CHIP responds well to canakinumab, a monoclonal antibody that targets the cytokine IL-1 beta. Tet2 and other mutations can modulate expression of a variety of cytokines and chemokines, which increases the risk of cardiovascular disease.

Random mutations in multiple genes promote clonal expansion of hematopoietic stem cells (HSCs) through a variety of mechanisms, said Siddhartha Jaiswal, MD, PhD, Assistant Professor of Pathology in the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine. Research in mouse models and human cell cultures has found that some mutations promote tumor growth while others are protective.

“HSCs form a continuum from a highly proliferative state to an arrested state,” Jaiswal explained. “CHIP driver mutations are like a cheat code that unlocks TCL1A expression and avoids stress responses that can inhibit proliferation. Mutations in Tet2, ASXL1, SF3B1, and SRSF2 promote the TCL1A protein and drive clonal expansion to promote proliferation and cancer.”

Jennifer J. Trowbridge, PhD
Jennifer J. Trowbridge, PhD

One reason CH is more common in older individuals is the gradual increase in senescent cells favoring expansion of CH-mutated HSCs, explained Jennifer J. Trowbridge, PhD. Multiple DNMT3A mutations are seen in human acute myeloid leukemia. Using a mouse model, she found that DNMT3A-mutant cells have higher long-term engraftment in older recipients than in younger mice. Crosstalk between DNMT3A-mutant cells and the bone marrow microenvironment promotes CH, she noted.

“We see a strong enrichment for senescence, especially in mesenchymal stem cells and not in endothelial cells,” said Trowbridge, Professor and the Dattels Family Chair at The Jackson Laboratory. “DNMT3A-mutant hematopoiesis induces senescence in mesenchymal cells.”

Depleting senescent mesenchymal cells with navitoclax, a dual BCL-2 and BCL-xL inhibitor that is not used clinically, does not alter normal hematopoiesis but dramatically reduces DNMT3A-mutant hematopoiesis and delays progression to myeloid leukemia, she noted.

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