title: Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia.
abstract: Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small-molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1-110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.
authors.affiliation: Children's Hospital Los Angeles, Division of Hematology and Oncology, Department of Pediatrics, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Gang
authors.affiliation: Children's Hospital Los Angeles, Division of Hematology and Oncology, Department of Pediatrics, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Hsieh
authors.affiliation: Children's Hospital Los Angeles, Division of Hematology and Oncology, Department of Pediatrics, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pham
authors.affiliation: Department of Biochemistry and Molecular Biology, Department of Molecular Pharmacology and Toxicology, Norris Comprehensive Cancer Center, Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, Department of Molecular Pharmacology and Toxicology, Norris Comprehensive Cancer Center, Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Children's Hospital Los Angeles, Division of Hematology and Oncology, Department of Pediatrics, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Huantes
authors.affiliation: Children's Hospital Los Angeles, Division of Hematology and Oncology, Department of Pediatrics, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Park
authors.affiliation: Children's Hospital Los Angeles, Division of Hematology and Oncology, Department of Pediatrics, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Naing
authors.affiliation: Department of Laboratory Medicine, Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Klemm
authors.affiliation: Department of Laboratory Medicine, Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Centre for Blood Research (CBR), Faculty of Medicine, Division of Hematology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: E M
authors.initials: EM
authors.lastname: Conway
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Pelus
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Crispino
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Department of Biochemistry and Molecular Biology, Department of Molecular Pharmacology and Toxicology, Norris Comprehensive Cancer Center, Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: McMillan
authors.affiliation: Department of Laboratory Medicine, Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Department of Biochemistry and Molecular Biology, Department of Molecular Pharmacology and Toxicology, Norris Comprehensive Cancer Center, Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kahn
authors.affiliation: Children's Hospital Los Angeles, Division of Hematology and Oncology, Department of Pediatrics, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Y-M
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001215:Asparaginase / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011744:Pyrimidinones / Q000494:pharmacology*; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D014750:Vincristine / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; C495270:CTNNB1 protein, human; C492448:ICG 001; D051034:Inhibitor of Apoptosis Proteins; D010446:Peptide Fragments; D011744:Pyrimidinones; D012795:Sialoglycoproteins; D000077022:Survivin; D051176:beta Catenin; C571744:bone sialoprotein (35-62), human; D014750:Vincristine; D003907:Dexamethasone; D001215:Asparaginase