J Cancer 2019; 10(16):3842-3850. doi:10.7150/jca.33989 This issue Cite
Research Paper
1. Department of Hematology, Zhongda Hospital, Medical School of Southeast University, Institute of Hematology Southeast University,Nanjing 210009, China
2. International Cooperative Leukemia Group and International Cooperative Laboratory of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
3. Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA17033, USA
4. Genome Sciences and Bioinformatics Core Facility, Institute for Personalized Medicine, Penn State College of Medicine, Hershey, PA17033, USA
The recombination mediated by recombination activating gene (RAG) is not only the dominant mutational process but also the predominant driver of oncogenic genomic rearrangement in acute lymphoblastic leukemia (ALL). It is further responsible for leukemic clonal evolution. In this study, significant RAG1 increase is observed in the subsets of B-ALL patients, and high expression of RAG1 is observed to be correlated with high proliferation markers. IKZF1-encoded protein, IKAROS, directly binds to the RAG1 promoter and regulates RAG1 expression in leukemic cells. CK2 inhibitor by increasing IKAROS activity significantly suppresses RAG1 expression in ALL in an IKAROS-dependent manner. Patients with IKZF1 deletion have significantly higher expression of RAG1 compared to that without IKZF1 deletion. CK2 inhibitor treatment also results in an increase in IKZF1 binding to the RAG1 promoter and suppression of RAG1 expression in primary ALL cells. Taken together, these results demonstrate that RAG1 high expression is associated with high proliferation markers in B-ALL. Our data for the first time proved that RAG1 expression is directly suppressed by IKAROS. Our results also reveal drive oncogenesis of B-ALL is driven by high expression of RAG1 with IKAROS dysfunction together, which have significance in an integrated prognostic model for adult ALL.
Keywords: RAG1, IKZF1, adult, acute lymphoblastic leukemia