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.