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| Status |
Public on Nov 27, 2020 |
| Title |
Ikaros and CK2 regulate expression of Bcl-xL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the Ikaros tumor suppressor. In leukemia, Ikaros’ function is impaired by oncogenic Casein Kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces Ikaros binding to the promoter of its target gene, particularly Bcl-xL. This results in a loss of Ikaros-mediated repression of Bcl-xL and in increased expression of Bcl-xL. Increased expression of Bcl-xL and/or CK2, as well as reduced Ikaros expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, enhances Ikaros-mediated repression of Bcl-xL and increases sensitivity to doxorubicin. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia and lays the groundwork for clinical testing of CK2 inhibitors in combination with doxorubicin for the treatment of hematopoietic malignancies.
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| Overall design |
Examine the genome-wide binding of Ikaros in JM-1, REH and 697 B-ALL leukemia cells and also the effect of CK2 inhibitor-CX-4945 on the Ikaros binding profiling in JM-1 cells.
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| Contributor(s) |
Song C, Ge Z, Ding Y, Kawasawa YI, Dovat S |
| Citation(s) |
32396934, 33531656 |
| Submission date |
Dec 06, 2019 |
| Last update date |
Jun 03, 2021 |
| Contact name |
chunhua song |
| E-mail(s) |
csong@hmc.psu.edu
|
| Phone |
717-531-1841
|
| Organization name |
Pennsyvania State University College of Medicine
|
| Department |
Pediatrics
|
| Street address |
500 University Drive
|
| City |
Hershey |
| State/province |
PA |
| ZIP/Postal code |
17033 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA593992 |
| SRA |
SRP234975 |
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