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

Morichika Takita; Fujiko Tsukahara; Taishi Mishima; Katsuaki Ieguchi; Masayuki Yamada; Hiroaki Honda; Yoshiro Maru

doi:10.18632/oncotarget.25849

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

Oncotarget. 2018 Aug 3;9(60):31682-31696. doi: 10.18632/oncotarget.25849.

Authors

Morichika Takita^#¹, Fujiko Tsukahara^#¹, Taishi Mishima¹, Katsuaki Ieguchi¹, Masayuki Yamada^{1

2}, Hiroaki Honda³, Yoshiro Maru¹

Affiliations

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.

^# Contributed equally.

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.

Keywords: Imatinib; cell death; chronic myeloid leukemia; differentiation; p210BCR-ABL.