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Title: Targeting of the BLT2 in chronic myeloid leukemia inhibits leukemia stem/progenitor cell function

Abstract

Imatinib, a tyrosine kinase inhibitor (TKI) has significantly improved clinical outcome for chronic myeloid leukemia (CML) patients. However, patients develop resistance when the disease progresses to the blast phase (BP) and the mechanisms are not well understood. Here we show that BCR-ABL activates BLT2 in hematopoietic stem/progenitor cells to promote leukemogenesis and this involves the p53 signaling pathway. Compared to normal bone marrow (NBM), the mRNA and protein levels of BLT2 are significantly increased in BP-CML CD34{sup +} stem/progenitor cells. This is correlated with increasing BCR-ABL expression. In contrast, knockdown of BCR-ABL or inhibition of its tyrosine kinase activity decreases Blt2 protein level. BLT2 inhibition induces apoptosis, inhibits proliferation, colony formation and self-renewal capacity of CD34{sup +} cells from TKI-resistant BP-CML patients. Importantly, the inhibitory effects of BCR-ABL TKI on CML stem/progenitor cells are further enhanced upon combination with BLT2 inhibition. We further show that BLT2 activation selectively suppresses p53 but not Wnt or BMP-mediated luciferase activity and transcription. Our results demonstrate that BLT2 is a novel pathway activated by BCR-ABL and critically involved in the resistance of BP-CML CD34{sup +} stem/progenitors to TKIs treatment. Our findings suggest that BLT2 and p53 can serve as therapeutic targets for CML treatment.more » - Highlights: • BCR-ABL regulates BLT2 expression to promote leukemogenesis. • BLT2 is essential to maintain CML cell function. • Activation of BLT2 suppresses p53 signaling pathway in CML cells. • Inhibition of BLT2 and BCR-ABL synergize in eliminating CML CD34{sup +} stem/progenitors.« less

Authors:
; ;  [1]; ;  [2];  [3]
  1. Department of Laboratory Medicine, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China)
  2. Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou (China)
  3. Department of Neurosurgery, JingZhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou (China)
Publication Date:
OSTI Identifier:
22596327
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 472; Journal Issue: 4; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; BONE MARROW; CELL PROLIFERATION; COLONY FORMATION; INHIBITION; LEUKEMOGENESIS; LUCIFERASE; MESSENGER-RNA; MYELOID LEUKEMIA; PATIENTS; SKELETON; TYROSINE

Citation Formats

Xiao, Meifang, Ai, Hongmei, Li, Tao, Rajoria, Pasupati, Shahu, Prakash, and Li, Xiansong. Targeting of the BLT2 in chronic myeloid leukemia inhibits leukemia stem/progenitor cell function. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.03.018.
Xiao, Meifang, Ai, Hongmei, Li, Tao, Rajoria, Pasupati, Shahu, Prakash, & Li, Xiansong. Targeting of the BLT2 in chronic myeloid leukemia inhibits leukemia stem/progenitor cell function. United States. https://doi.org/10.1016/J.BBRC.2016.03.018
Xiao, Meifang, Ai, Hongmei, Li, Tao, Rajoria, Pasupati, Shahu, Prakash, and Li, Xiansong. 2016. "Targeting of the BLT2 in chronic myeloid leukemia inhibits leukemia stem/progenitor cell function". United States. https://doi.org/10.1016/J.BBRC.2016.03.018.
@article{osti_22596327,
title = {Targeting of the BLT2 in chronic myeloid leukemia inhibits leukemia stem/progenitor cell function},
author = {Xiao, Meifang and Ai, Hongmei and Li, Tao and Rajoria, Pasupati and Shahu, Prakash and Li, Xiansong},
abstractNote = {Imatinib, a tyrosine kinase inhibitor (TKI) has significantly improved clinical outcome for chronic myeloid leukemia (CML) patients. However, patients develop resistance when the disease progresses to the blast phase (BP) and the mechanisms are not well understood. Here we show that BCR-ABL activates BLT2 in hematopoietic stem/progenitor cells to promote leukemogenesis and this involves the p53 signaling pathway. Compared to normal bone marrow (NBM), the mRNA and protein levels of BLT2 are significantly increased in BP-CML CD34{sup +} stem/progenitor cells. This is correlated with increasing BCR-ABL expression. In contrast, knockdown of BCR-ABL or inhibition of its tyrosine kinase activity decreases Blt2 protein level. BLT2 inhibition induces apoptosis, inhibits proliferation, colony formation and self-renewal capacity of CD34{sup +} cells from TKI-resistant BP-CML patients. Importantly, the inhibitory effects of BCR-ABL TKI on CML stem/progenitor cells are further enhanced upon combination with BLT2 inhibition. We further show that BLT2 activation selectively suppresses p53 but not Wnt or BMP-mediated luciferase activity and transcription. Our results demonstrate that BLT2 is a novel pathway activated by BCR-ABL and critically involved in the resistance of BP-CML CD34{sup +} stem/progenitors to TKIs treatment. Our findings suggest that BLT2 and p53 can serve as therapeutic targets for CML treatment. - Highlights: • BCR-ABL regulates BLT2 expression to promote leukemogenesis. • BLT2 is essential to maintain CML cell function. • Activation of BLT2 suppresses p53 signaling pathway in CML cells. • Inhibition of BLT2 and BCR-ABL synergize in eliminating CML CD34{sup +} stem/progenitors.},
doi = {10.1016/J.BBRC.2016.03.018},
url = {https://www.osti.gov/biblio/22596327}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 4,
volume = 472,
place = {United States},
year = {Fri Apr 15 00:00:00 EDT 2016},
month = {Fri Apr 15 00:00:00 EDT 2016}
}