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

Manuela Mancini _, Simona Soverini, Gabriele Gugliotta, Maria Alessandra Santucci, Gianantonio Rosti, Michele Cavo, Giovanni Martinelli and Fausto Castagnetti

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Oncotarget. 2017; 8:88244-88250. https://doi.org/10.18632/oncotarget.21166

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Manuela Mancini1, Simona Soverini1, Gabriele Gugliotta1, Maria Alessandra Santucci1, Gianantonio Rosti1, Michele Cavo1, Giovanni Martinelli1 and Fausto Castagnetti1

1Department of Experimental Diagnostic and Specialty Medicine, DIMES–Institute of Hematology “L. and A. Seràgnoli”, University of Bologna Medical School, Bologna, Italy

Correspondence to:

Manuela Mancini, email: [email protected]

Keywords: chibby1, ß-catenin, ER stress, autophagy, BCR-ABL1

Received: March 31, 2017     Accepted: August 04, 2017     Published: September 22, 2017


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.

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