UC San Diego

Acute myeloid leukemia (AML) is one of the deadliest forms of leukemia, a prominent cancer in the United States, with a five-year survival rate ranging from 15%-70%. Myelodysplastic syndromes (MDS) are a group of hematopoietic malignancies, which can lead to AML. Recently, it was found that mutations in the splicing factor SRSF2 are present in over 20% of MDS patients. To understand the molecular mechanism of how SRSF2 mutations contribute to blood disorders, we used Srsf2 conditional knockout (KO) mice (Srsf2 f/f) to examine the role of SRSF2 in steady-state and stress hematopoiesis. Blood cell -specific Srsf2 KO (Vav-Cre/Srsf2 f/f) was embryonic lethal between embryonic day 16 and 18. Furthermore, SRSF2 deficient fetal liver cells showed increased apoptosis and G1 cell cycle arrest. To study SRSF2 deficiency in hematopoiesis of adult mice, we created double stranded RNA poly-IC inducible KO mice by breeding Mx1-Cre with Srsf2 f/f mice. Unexpectedly, after poly-IC injection Mx1- Cre/Srsf2 f/f mice are alive. In addition, there is no phenotype in heterozygous Srsf2 KO (Srsf2 +/-) mice in steady state. To evaluate the effect of haploinsufficiency under stress condition, mice with Srsf2+/- blood cells were injected weekly with the chemotherapeutic drug 5- flurouracil or underwent single sub-lethal dose of irradiation. Experiment that would elucidate the mechanism of the disease were performed as well, which include bone marrow transplantation of SRSF2 overexpressed cells, bone marrow transplantation of Mx1-Cre/ Srsf2 f/f, andMx1-Cre/ Srsf2 +/f cells followed by poly-IC injection, and RNA sequencing of lineage-depleted bone marrow cells that overexpress wild-type and mutant SRSF2. Through these in vitro and in vivo experiments we aim to analyze the role of SRSF2 in the blood system and in the development of MDS