Abstract
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 (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS' function is impaired by oncogenic casein kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and 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, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multidrug-resistant B-ALL. 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. These data lay the groundwork for clinical testing of a rationally designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.
Original language | English (US) |
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Pages (from-to) | 1520-1534 |
Number of pages | 15 |
Journal | Blood |
Volume | 136 |
Issue number | 13 |
DOIs | |
State | Published - Sep 24 2020 |
Funding
This work was supported by grants from National Institutes of Health, National Cancer Institute R01CA209829 (K.J.P. and S.D.), R01CA213912 (S.D. and C.S.), F30CA221109 (J.L.P.), National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110108) and National Cancer Institute (R01CA204044) (S.H.), and National Institute of General Medical Sciences (R35GM124820) and National Human Genome Research Institute (R01HG009906) (F.Y.); National Center for Advancing Translational Sciences (KL2 TR002015) (C.G.); Hyundai Hope on Wheels Scholar Grant (C.G.); National Natural Science Foundation of China (81770172) (Z.G.); Four Diamonds Fund of the Pennsylvania State University College of Medicine (S.D., C.G., and C.S.); Bear Necessities Pediatric Cancer Foundation; Alex's Lemonade Stand Foundation (S.D.), John Wawrynovic Leukemia Research Scholar Endowment (S.D. and C.G.); St. Baldrick's Foundation (S.D. and C.G.); and Rally Foundation (C.G.). This work was supported by grants from National Institutes of Health, National Cancer Institute R01CA209829 (K.J.P. and S.D.), R01CA213912 (S.D. and C.S.), F30CA221109 (J.L.P.), National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110108) and National Cancer Institute (R01CA204044) (S.H.), and National Institute of General Medical Sciences (R35GM124820) and National Human Genome Research Institute (R01HG009906) (F.Y.); National Center for Advancing Translational Sciences (KL2 TR002015) (C.G.); Hyundai Hope on Wheels Scholar Grant (C.G.); National Natural Science Foundation of China (81770172) (Z.G.); Four Diamonds Fund of the Pennsylvania State University College of Medicine (S.D., C.G., and C.S.); Bear Necessities Pediatric Cancer Foundation; Alex’s Lemonade Stand Foundation (S.D.), John Wawrynovic Leukemia Research Scholar Endowment (S.D. and C.G.); St. Baldrick’s Foundation (S.D. and C.G.); and Rally Foundation (C.G.).
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology