Abstract 4051: Loss of nuclear beta catenin, following chibby enforced expression, activates endoplasmic reticulum stress in cells expressing the BCR-ABL1 fusion gene of chronic myeloid leukemia.

Abstract

Abstract CML is a myeloproliferative disease originated from a pluripotent hematopoietic cell, the bona fide leukemic stem cell (LSC), where reciprocal translocation t(9;22) generates the BCR-ABL rearranged gene. This single genetic lesion drives the clonal expansion of leukemic hematopoiesis through the constitutively activated tyrosine kinase (TK) of its protein. The majority of CML patients undergoes complete hematologic remission in response to TK inhibitor Imatinib (IM). However, BCR-ABL+ LSC are neither dependent on BCR-ABL TK for proliferation and survival nor killed by IM and second generation inhibitors, providing a putative source of drug-resistance. β catenin is a central component of BCR-ABL+ LSC self-renewal. Moreover, it may have a role in the stemness recovery of committed granulocyte/macrophage progenitors at the outcome of blast crisis. Consequently, beta catenin subcellular distribution is a central component of signaling activity and its nuclear-cytoplasmatic shuttling is tightly regulated by multiple carrier protein, including 14-3-3. Chibby (CBY) is a protein that directly interacts with beta catenin and competes with TCF/LEF factors for beta catenin binding, repressing its transcriptional activity. Moreover, Chibby cooperates with 14-3-3 to regulate beta catenin subcellular distribution and signaling activity. We have recently found a significant CBY reduction associated with BCR-ABL TK with a consequent increment of active beta catenin. This findings suggested a CBY putative role in the proliferative advantage of CML hematopoiesis and addressed our further investigation towards the CBY impact on proliferation and survival of BCR-ABL+ cells. To this purpose we stably transduced the BCR-ABL+ K562 cell line with a construct containing C22orf2. The cytoplasmatic accumulation of beta catenin triggered the endoplasmic reticulum (ER)-associated stress pathway known as the unfolded protein response (UPR). The UPR is primarily a survival response which activates a series of complementary adaptive mechanisms to resolve the dysregulation of protein folding. However, under prolonged and irreversible ER stress conditions UPR triggers apoptosis through caspase activation and modulation of ER Ca2+ signaling. The ER stress elicited by beta catenin cytoplasmatic accumulation in consequence of CBY overexpression doomed K562 cells to apoptotic death induced by a significant increase of CHOP, which amplifies the pro-apoptotic signal by transcriptional activation of BIM and the release of PKR-like eIF2 kinase (PERK) and inositol-requiring enzyme (IRE1), all mediators of ER stress. Our results suggest that enforced CBY expression significantly reduced K562 proliferation through events encompassing the beta catenin prominent relocation to the cytoplasm and its transcriptional silencing. Citation Format: Manuela Mancini, Elisa Leo, Enrica Borsi, Fausto Castagnetti, Michelangelo Fiorentino, Ilaria Iacobucci, Michele Cavo, Maria Alessandra Santucci, Giovanni Martinelli. Loss of nuclear beta catenin, following chibby enforced expression, activates endoplasmic reticulum stress in cells expressing the BCR-ABL1 fusion gene of chronic myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4051. doi:10.1158/1538-7445.AM2013-4051