Role of Jak mutations in production of reactive oxygen species and DNA damage in a mouse model of precursor B cell acute lymphoblastic leukemia induced by PU.1 and Spi-B deletion

Acute Lymphoblastic Leukemia (ALL) is the most frequently occurring type of cancer in young children. Despite a high remission rate, ALL is still the leading cause of cancer-related deaths in children, and much needs to be done to reduce the long-term effects of chemotherapy. 80% of pediatric ALLs are cancers of the B lymphocyte lineage (B-ALL), and of these 60% involve mutation or chromosomal translocation of genes encoding transcription factors. Development of B-ALL is thought to be caused by initiating genetic lesions in developing progenitor/precursor B cells that function as drivers for accumulation of additional mutations, leading to oncogenic transformation by an evolutionary selection process. A paradigm-shifting change during the past decade is that whole genome sequencing, whole exome sequencing, and targeted cancer gene sequencing has eliminated the bottleneck in identifying mutations that might function as drivers of leukemogenesis. However, there is still an gap in utilizing biochemistry and mouse models to determine the molecular mechanisms of how identified mutations function as drivers of leukemogenesis. Mouse models are still critically important for understanding leukemogenesis; and this project utilizes an innovative mouse model for pre-B-ALL. Our mouse model has deletions of SpiB and PU.1, key transcription factors for B-cell development. When the mice develop B-ALL, we isolated DNA and RNA from their thymic leukemias. DNA and RNA were then subjected to whole exome sequencing and RNA-sequencing, respectively, to reveal high-frequency mutations and transcriptional changes.