Journal
ONCOTARGET
Volume 8, Issue 50, Pages 88244-88250Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.21166
Keywords
chibby1; beta-catenin; ER stress; autophagy; BCR-ABL1; chronic myeloid leukemia
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Funding
- University of Bologna [RFO funds]
- Ministero della Pubblica Istruzione e della Ricerca [PRIN funds]
- Umberto Veronesi Foundation
- AIRC
- FP7 NGS-PTL project
- Progetto Regione-Universita
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Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as beta-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on beta-catenin involves the direct interaction with: The C-terminal activation domain of beta-catenin, which hinders beta-catenin binding with Tcf/Lef transcription factors hence repressing beta-catenin transcriptional activation. 14-3-3 scaffolding proteins (sigma or xi), which drive CBY1 nuclear export into a stable tripartite complex with beta-catenin. The relative proximity of C22orf2 gene encoding for CBY1 to the BCR breakpoint on chromosome 22q11, whose translocation and rearrangement with the c-ABL is the causative event of chronic myeloid leukemia (CML), suggested that gene haploinsufficiency may play a role in the disease pathogenesis and progression. We found CBY1 down-modulation associated with the BCR-ABL1, promoted by transcriptional mechanisms (promoter hyper-methylation) and post-transcriptional events, addressing the protein towards proteasome-dependent degradation through SUMOylation. CBY1 reduced expression in clonal progenitors and, more importantly, in leukemic stem cells (LSC), is contingent upon the tyrosine kinase (TK) activity of BCR-ABL1 fusion protein. Accordingly, its induction by Imatinib (IM) and second generation TK inhibitors contributes to beta-catenin inactivation through multiple events encompassing the activation of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) and autophagy, eventually leading to apoptotic death. These findings support the advantage of combined regimens including drugs targeting DNA epigenetics and/or proteasome to eradicate the BCR-ABL1+ hematopoiesis.
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