IKAROS and CK2 regulate expression of BCL-XL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia.
Animals
Antibiotics, Antineoplastic
/ pharmacology
Casein Kinase II
/ genetics
Cell Line, Tumor
Doxorubicin
/ pharmacology
Drug Resistance, Neoplasm
Gene Expression Regulation, Leukemic
/ drug effects
Humans
Ikaros Transcription Factor
/ genetics
Mice
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ drug therapy
bcl-X Protein
/ genetics
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
24 09 2020
24 09 2020
Historique:
received:
30
07
2019
accepted:
23
04
2020
pubmed:
13
5
2020
medline:
23
3
2021
entrez:
13
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32396934
pii: S0006-4971(20)61687-1
doi: 10.1182/blood.2019002655
pmc: PMC7515690
doi:
Substances chimiques
Antibiotics, Antineoplastic
0
BCL2L1 protein, human
0
IKZF1 protein, human
0
bcl-X Protein
0
Ikaros Transcription Factor
148971-36-2
Doxorubicin
80168379AG
Casein Kinase II
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1520-1534Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL151195
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009906
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK110108
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204044
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR002015
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA221109
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213912
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193167
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002014
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA209829
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA243167
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124820
Pays : United States
Informations de copyright
© 2020 by The American Society of Hematology.
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