Mancini Manuela, Soverini Simona, Gugliotta Gabriele, Santucci Maria Alessandra, Rosti Gianantonio, Cavo Michele, Martinelli Giovanni, Castagnetti Fausto
Department of Experimental Diagnostic and Specialty Medicine, DIMES-Institute of Hematology "L. and A. Seràgnoli", University of Bologna Medical School, Bologna, Italy.
Oncotarget. 2017 Sep 22;8(50):88244-88250. doi: 10.18632/oncotarget.21166. eCollection 2017 Oct 20.
Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as β-catenin antagonist. CBY1 is encoded by (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 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 , 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.
奇比1（CBY1）是一种小型且进化保守的蛋白质，它作为β-连环蛋白拮抗剂发挥作用。CBY1由（22q13.1）编码。它对β-连环蛋白的拮抗功能涉及与以下物质的直接相互作用：β-连环蛋白的C端激活结构域，这会阻碍β-连环蛋白与Tcf/Lef转录因子结合，从而抑制β-连环蛋白的转录激活；14-3-3支架蛋白（σ或ξ），其促使CBY1核输出进入与β-连环蛋白形成的稳定三方复合物。编码CBY1的基因与22号染色体q11上的BCR断点相对接近，其与c-ABL的易位和重排是慢性髓性白血病（CML）的致病事件，这表明基因单倍体不足可能在疾病的发病机制和进展中起作用。我们发现CBY1的下调与转录机制（启动子高甲基化）和转录后事件相关，通过SUMO化使蛋白质走向蛋白酶体依赖性降解。CBY1在克隆祖细胞中，更重要的是在白血病干细胞（LSC）中表达降低，这取决于BCR-ABL1融合蛋白的酪氨酸激酶（TK）活性。因此，伊马替尼（IM）和第二代TK抑制剂对其的诱导通过包括激活内质网（ER）应激相关的未折叠蛋白反应（UPR）和自噬在内的多个事件导致β-连环蛋白失活，最终导致凋亡死亡。这些发现支持了包括靶向DNA表观遗传学和/或蛋白酶体的药物的联合治疗方案在根除BCR-ABL1+造血方面的优势。
