Joseph Collins, PhD, Postdoctoral Fellow

Blood stem cells accumulate mutations over a lifetime. These mutations can give an advantage to individual stem cells leading to the accumulation of mutant blood cells, in a condition termed clonal hematopoiesis (CH) which is notably common among the elderly, affecting approximately 13% of individuals over the age of 70. CH predisposes those individuals to blood cancers and blood clots. Dr. Zon’s laboratory has developed an in vivo model that recapitulates CH seen in humans and use color-based cellular barcoding to label blood stem cells and their progeny. Currently, there are no therapies to remove these mutant, disease-initiating blood stem cells.

Recently, Dr. Zon’s laboratory discovered that macrophages perform quality assurance of blood stem cells during embryonic
development. Macrophages either kill or promote stem cell proliferation on the basis of proteins expressed on their surface. Calreticulin signals the macrophage to kill the blood stem cell whereas Beta-2-microglobulin (B2m) counters that signal to direct macrophage-mediated blood stem cell proliferation. Furthermore, Dr. Zon’s laboratory discovered that B2m is activated by toll-like receptor 3 (TLR3) binding to endogenous double-stranded RNA (dsRNA).

Dr. Collins’ project aims to co-opt these embryonic programs to support healthy stem cells and eliminate mutant, disease-causing blood stem cells in vivo. In aim 1 of his project, he will investigate the endogenous dsRNA which binds TLR3 to activate protective B2m signaling in blood stem cells. In aim 2, he will selectively activate Calreticulin, but not B2m, in mutant, malignancy-causing stem cells to selectively eliminate mutants in vivo by macrophages. Through his proposed work, Dr. Collins aims to develop revolutionary cancer immunology treatments in adults and provide a new therapy for CH and myeloid disorders.

Projects and Grants

Co-opting macrophage-mediated HSPC quality assurance mechanisms to eliminate mutant blood stem cells in clonal hematopoiesis

Boston Children’s Hospital | Blood Cancers | 2025 | Leonard Zon, MD