Chibby 1: a new component of β-catenin-signaling in chronic myeloid leukemia

// Manuela Mancini 1 , Simona Soverini 1 , Gabriele Gugliotta 1 , Maria Alessandra Santucci 1 , Gianantonio Rosti 1 , Michele Cavo 1 , Giovanni Martinelli 1 and Fausto Castagnetti 1 1 Department of Experimental Diagnostic and Specialty Medicine, DIMES–Institute of Hematology “L. and A. Seragnoli”, University of Bologna Medical School, Bologna, Italy Correspondence to: Manuela Mancini, email: mancini_manu@yahoo.com Keywords: chibby1, s-catenin, ER stress, autophagy, BCR-ABL1 Received: March 31, 2017 Accepted: August 04, 2017 Published: September 22, 2017 ABSTRACT Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as β-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on β-catenin involves the direct interaction with: The C-terminal activation domain of β-catenin, which hinders β-catenin binding with Tcf/Lef transcription factors hence repressing β-catenin transcriptional activation. 14-3-3 scaffolding proteins (σ or ξ), which drive CBY1 nuclear export into a stable tripartite complex with β-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 β-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.