Regulation of gene expression in Acute Lymphoblastic Leukemia by Ikaros tumor suppressor gene

open_access
Open Access
Author:
Kane, Shriya Gopal
Area of Honors:
Science
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Sinisa Dovat, Thesis Supervisor
Sairam V Rudrabhatla, Thesis Honors Advisor
Keywords:
Ikaros
Acute Lymphoblastic Leukemia
Casein Kinase 2
Abstract:
Acute lymphoblastic leukemia (ALL) is the most frequent cause of childhood malignancy. In the United States alone, during this year, over 3,000 children and adolescents will be diagnosed with ALL. The therapy for ALL has dramatically improved over the last 50 years, which results in an overall survival rate of 90% in children. However, the survival rate for the relapsed leukemia has not changed over the last 30 years and has remained at 50%. Thus, there is a need to develop a novel treatment approach to ALL. Ikaros, a DNA binding protein, functions as a tumor suppressor in pediatric and adult ALL, and impaired Ikaros activity is associated with the development of a high-risk ALL. It is therefore imperative to understand how Ikaros regulates cellular proliferation in ALL in order to design a targeted treatment for this disease. Previous studies have shown that inhibition of Casein Kinase 2 (CK2) results in the suppression of leukemia in cases of B cell ALL (B-ALL). Target therapies that employ CK2 inhibitors have been successful in regulating and controlling the epigenetic signature of B-ALL by exploiting CK2’s effect on Ikaros. The previous studies have thus provided a rationale to test the effect of CK2 inhibition on Ikaros in T cell ALL. The hypotheses that Ikaros represses transcription of the genes that are essential for the cell cycle progression in T-ALL and that inhibition of CK2 in T-ALL enhances Ikaros-mediated regulation of the cell cycle progression resulting in a cytotoxic effect on T-ALL cells were tested. Results of the conducted experiments demonstrated that Ikaros represses expression of Cell Division Controller gene 2 (CDC2) and Cell Division Cycle gene 7 (CDC7) in T-cell leukemia. CK2 impairs Ikaros function, whereas its inhibition restores Ikaros function, providing evidence that supports the use of CK2 specific target therapy for T-ALL.