Constitutively active CaMKII Drives B lineage acute lymphoblastic leukemia/lymphoma in tp53 mutant zebrafish

Acute lymphoblastic leukemia/lymphoma (ALL) is the most common pediatric cancer and is a malignancy of T or B lineage lymphoblasts. Dysregulation of intracellular Ca2+ levels has been observed in patients with ALL, leading to improper activation of downstream signaling. Here we describe a new zebrafish model of B ALL, generated by expressing human constitutively active CaMKII (CA-CaMKII) in tp53 mutant lymphocytes. In this model, B cell hyperplasia in the kidney marrow and spleen progresses to overt leukemia/lymphoma, with only 29% of zebrafish surviving the first year of life. Leukemic fish have reduced productive genomic VDJ recombination in addition to reduced expression and improper splicing of ikaros1, a gene often deleted or mutated in patients with B ALL. Inhibiting CaMKII in human pre-B ALL cells induced cell death, further supporting a role for CaMKII in leukemogenesis. This research provides novel insight into the role of Ca2+-directed signaling in lymphoid malignancy and will be useful in understanding disease development and progression. Acute lymphoblastic leukemia/lymphoma (ALL) is the most common pediatric cancer, representing approximately 3,000 new cases annually in patients under the age of 20 in the United States. Although survival rates for ALL are approximately 92%, there still remains a subset of cases that have poor outcomes that require novel model systems to understand disease etiology and identify novel targets for drug discovery. Our research identified calcium/calmodulin-dependent protein kinase, CaMKII, as a critical mediator of B cell ALL maturation. We found that zebrafish expressing activated CaMKII on a tp53 mutant background developed B cell ALL, with cancer cells visible in the marrow, spleen, and blood. These fish incorrectly expressed a key gene, ikaros1, which is often mutated or deleted in patients with B cell ALL. We also determined that treating human B ALL cells in culture with a drug targeting CaMKII caused the malignant cells to die. These results identified CaMKII as a key gene in B ALL development and a possible target for therapeutic intervention.