The 9th International Forum on Stem Cells (IFSC) in 2024 focused on basic stem cell research, regenerative medicine, cell therapy, and the application of clinical research guidelines, gathering experts and scholars from around the world to discuss the latest frontiers of scientific discoveries and technological advancements. During the conference, "Hematology Frontier" specially invited Dr. Rafael Bejar from UC San Diego Health to share his exploration in the field of clonal hematopoiesis, from biological phenomena to clinical challenges.

Hematology Frontier：Clonal Hematopoiesis is increasingly recognized for its clinical significance. Could you briefly explain the concept of clonal hematopoiesis and its role in hematological disorders?

Dr. Rafael Bejar：Absolutely. So clonal hematopoiesis describes a process in which a mutation occurs in a hematopoietic stem cell that allows that hematopoietic stem cell to grow and proliferate more than its normal counterparts. It can actually reach a substantial fraction of all the blood cells in the blood being derived from a mutant clonal cell. Now that in and of itself is not a disease, but it is often a precursor to disorders, like myelodysplastic syndromes or acute leukemia, which are also driven by the acquisition of mutations in hematopoietic stem cells

Hematology Frontier：In your latest report, you mentioned therapeutic targets for clonal hematopoiesis. Could you share your findings in this area, and what are the main strategies currently available for treating clonal hematopoiesis?

Dr. Rafael Bejar：Yes, there’s a strong interest in treating clonal hematopoiesis to prevent some of its negative health consequences. I mentioned that individuals with clonal hematopoiesis can go on to develop blood cancers, but they also have risks of inflammatory-related conditions, such as heart disease, lung disease, liver disease, and so on.If we have a mechanism for intervening with clonal hematopoiesis, we may be able to mitigate some of these negative health consequences. So far, we have really focused on treatments that target very specific mutations. But in the future, we would like to look at more broad mechanisms that can target multiple different kinds of mutated cells. And there’s interest in targeting anti-inflammatory pathways, as well as perhaps other pathways, like a gene that I mentioned, TCL1A, that can be overexpressed when these mutations are present. That might lead to a reduction in the size of the mutant clone.

Hematology Frontier：Finally, regarding the research on clonal hematopoiesis, what challenges do you think still exist? And what breakthroughs might we expect in this field in the next few years?

Dr. Rafael Bejar：There are several challenges that exist when we study clonal hematopoiesis. One of them is that we don’t always have good mouse or animal models for these conditions. So we really have to study them in humans. For example, splicing factor mutations don’t really replicate clonal hematopoiesis in animals very well. Yet they are the highest risk mutations when we see them in humans. The other challenge is that individuals who have clonal hematopoiesis generally feel they don’t have an abnormality that would require immediate therapy. So we have to develop therapies that are going to be very well tolerated and that don’t have a lot of side effects. And ultimately, these clinical trials are going to take a long time, because the transition from clonal hematopoiesis to a blood cancer can take many years. And often our clinical trials don’t have that long to wait. So we will need to develop better techniques for determining how effective drugs are using earlier surrogate endpoints, but that work is just beginning.