Paradoxical counteraction by imatinib against cell death in myeloid progenitor 32D cells expressing p210BCR-ABL

// Morichika Takita 1, * , Fujiko Tsukahara 1, * , Taishi Mishima 1 , Katsuaki Ieguchi 1 , Masayuki Yamada 1, 2 , Hiroaki Honda 3 and Yoshiro Maru 1 1 Department of Pharmacology, Tokyo Women’s Medical University, Tokyo, Japan 2 Center for Medical Education, Graduate School of Medicine, Kyoto University, Kyoto, Japan 3 Institute of Laboratory Animals, Tokyo Women’s Medical University, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Morichika Takita, email: mtakita@twmu.ac.jp Yoshiro Maru, email: maru.yoshiro@twmu.ac.jp Keywords: chronic myeloid leukemia; p210BCR-ABL; Imatinib; cell death; differentiation Received: February 06, 2018     Accepted: July 12, 2018     Published: August 03, 2018 ABSTRACT Chronic myeloid leukemia (CML) is believed to be caused by the tyrosine kinase p210BCR-ABL, which exhibits growth-promoting and anti-apoptotic activities. However, mechanisms that allow cell differentiation in CML still remain elusive. Here we established tetracycline (Tet)-regulatable p210BCR-ABL-expressing murine 32D myeloid progenitor (32D/TetOff-p210) cells to explore p210BCR-ABL-induced cell death and differentiation. Tet-regulatable overexpression of p210BCR-ABL induced cell death due to the activation of both caspase-1 and caspase-3, coincident with the differentiation from myeloid progenitors into CD11b + Ly6C + Ly6G + cells with segmented nuclei, exemplified as granulocytic myeloid-derived suppressor cells (G-MDSC), and the ability to secrete IL-1β, TNF-α, and S100A8/A9 into the culture supernatant. Treatment with imatinib almost completely abrogated all these phenotypes. Moreover, overexpression of a sensor of activated caspase-1 based on fluorescence resonance energy transfer (FRET) probe enabled us to detect activation of caspase-1 in a human CML cell line, K562. Furthermore, increased numbers of splenic G-MDSC associated with enhancement of S100A8/A9 production were observed in transgenic mice expressing p210BCR-ABL compared with that in wild-type mice. We also propose the novel mode of cell death in this 32D/TetOff-p210 system termed as myeloptosis.