Journal Article Epublish
PubMed: 38117861 DOI: 10.1371/journal.pgen.1011102
Constitutively active CaMKII Drives B lineage acute lymphoblastic leukemia/lymphoma in tp53 mutant zebrafish.
PLoS Genet 19(12):e1011102
Authors: Sarah C Rothschild, Guanhua Lai, Robert M Tombes, Wilson K Clements
Affiliations
- Life Sciences, Virginia Commonwealth University, Richmond, Virginia, United States of America.
- Pathology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
- Experimental Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Abstract
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.
MeSH
Cells, Genes, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Genetics, Lymphoma, Neoplasms, Leukemia, Calcium-Calmodulin-Dependent Protein Kinase Type 2