DNA damage, immune response, aging and leukemia

Hematopoiesis, the process to produce all types of blood cells, is regulated by both intrinsic and extrinsic signals, alterations of which affect blood stem cell function and potentially cause leukemia.  DNA damage and immune response are 2 important processes that play critical roles in genomic integrity and surveillance against tumors, including leukemia. As an important type of immune cells residing in the bone marrow (BM), macrophages play important roles in both physiological and pathological processes. Our previous studies suggest that immune receptor TREM1 promotes leukemia and immunotherapy resistance through favoring tumor-fostering M2 macrophage differentiation. It is generally believed that immune responses triggered by transient DNA damage are beneficial while those associated with long-lasting DNA damage are harmful. We recently show that NLRP12, a member of the NLR inflammasome family, is induced by persistent DNA damage to improve blood stem cell function, suggesting a protective role of NLRP12 in the context of immune response to persistent DNA damage under conditions of DNA repair deficiency and aging. BRCA2 (FANCD1) is involved in DNA double-strand break (DSB) repair, the mutant phenotypes of which are associated with increased cancer risk, mostly breast and ovarian cancer. Biallelic mutations in BRCA2 are responsible for ~3% of all cases of Fanconi Anemia (FA), a genetic disorder associated with developmental defects, progressive BM failure and high risk of developing cancers. We recently found that BRCA2 and SMAD3 act together to suppress the expression of PPAR, a key regulator of fat cell development and lipid storage, in BM mesenchymal stromal cells, therefore regulating the balance between bone forming and lipid accumulation, and supporting blood development. Error-free homologous recombination (HR) and error-prone non-homologous end-joining (NHEJ) are two major pathways to repair DNA double strand break (DSB), which is the most severe DNA lesion. We recently identified a stress-induced DSB repair complex that controls the balance between HR and NHEJ, a property that can be used to kill HR-sufficient leukemia. We will utilize novel mouse models to study the signaling pathways that promote leukemogenesis, with the focus on the crosstalk between DDR and immune response; stem cell-niche interaction; aging; stress-induced complex formation; thereby develop new approaches to improve blood stem cell function and for leukemia therapy.