Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia

E. J. Gang, Y. T. Hsieh, J. Pham, Y. Zhao, C. Nguyen, S. Huantes, E. Park, K. Naing, L. Klemm, S. Swaminathan, E. M. Conway, Louis Pelus, J. Crispino, C. G. Mullighan, M. McMillan, M. Müschen, M. Kahn, Y. M. Kim

Research output: Contribution to journalArticle

78 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2169-2178
Number of pages10
JournalOncogene
Volume33
Issue number17
DOIs
StatePublished - Apr 24 2014

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CREB-Binding Protein
Catenins
Drug Interactions
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Clone Cells
Transcriptional Activation
Inhibitor of Apoptosis Proteins
Inbred NOD Mouse
Mutation
Wnt Signaling Pathway
SCID Mice
Chromatin Immunoprecipitation
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Hematopoietic Stem Cells
Drug Resistance
Acute Myeloid Leukemia
Chromosome Aberrations
ICG 001
Leukemia
Stem Cells

Keywords

  • acute lymphoblastic leukemia
  • CBP
  • drug resistance
  • ICG-001
  • p300
  • small-molecule inhibitor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Gang, E. J., Hsieh, Y. T., Pham, J., Zhao, Y., Nguyen, C., Huantes, S., ... Kim, Y. M. (2014). Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene, 33(17), 2169-2178. https://doi.org/10.1038/onc.2013.169

Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. / Gang, E. J.; Hsieh, Y. T.; Pham, J.; Zhao, Y.; Nguyen, C.; Huantes, S.; Park, E.; Naing, K.; Klemm, L.; Swaminathan, S.; Conway, E. M.; Pelus, Louis; Crispino, J.; Mullighan, C. G.; McMillan, M.; Müschen, M.; Kahn, M.; Kim, Y. M.

In: Oncogene, Vol. 33, No. 17, 24.04.2014, p. 2169-2178.

Research output: Contribution to journalArticle

Gang, EJ, Hsieh, YT, Pham, J, Zhao, Y, Nguyen, C, Huantes, S, Park, E, Naing, K, Klemm, L, Swaminathan, S, Conway, EM, Pelus, L, Crispino, J, Mullighan, CG, McMillan, M, Müschen, M, Kahn, M & Kim, YM 2014, 'Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia', Oncogene, vol. 33, no. 17, pp. 2169-2178. https://doi.org/10.1038/onc.2013.169
Gang, E. J. ; Hsieh, Y. T. ; Pham, J. ; Zhao, Y. ; Nguyen, C. ; Huantes, S. ; Park, E. ; Naing, K. ; Klemm, L. ; Swaminathan, S. ; Conway, E. M. ; Pelus, Louis ; Crispino, J. ; Mullighan, C. G. ; McMillan, M. ; Müschen, M. ; Kahn, M. ; Kim, Y. M. / Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. In: Oncogene. 2014 ; Vol. 33, No. 17. pp. 2169-2178.
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