Oncotarget

Research Papers:

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 and Yoshiro Maru

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Oncotarget. 2018; 9:31682-31696. https://doi.org/10.18632/oncotarget.25849

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Abstract

Morichika Takita1,*, Fujiko Tsukahara1,*, Taishi Mishima1, Katsuaki Ieguchi1, Masayuki Yamada1,2, Hiroaki Honda3 and Yoshiro Maru1

1Department of Pharmacology, Tokyo Women’s Medical University, Tokyo, Japan

2Center for Medical Education, Graduate School of Medicine, Kyoto University, Kyoto, Japan

3Institute 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.


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