Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34 (+)CD38(-) stem and progenitor cells in chronic myeloid leukemia

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Dolinska , M , Piccini , A , Wong , W M , Gelali , E , Johansson , A-S , Klang , J , Xiao , P , Yektaei-Karin , E , Stromberg , U O , Mustjoki , S , Stenke , L , Ekblom , M & Qian , H 2017 , ' Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34 (+)CD38(-) stem and progenitor cells in chronic myeloid leukemia ' , Biochemical and Biophysical Research Communications , vol. 490 , no. 2 , pp. 378-384 . https://doi.org/10.1016/j.bbrc.2017.06.051

Title: Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34 (+)CD38(-) stem and progenitor cells in chronic myeloid leukemia
Author: Dolinska, Monika; Piccini, Alexandre; Wong, Wan Man; Gelali, Eleni; Johansson, Anne-Sofie; Klang, Johannis; Xiao, Pingnan; Yektaei-Karin, Elham; Stromberg, Ulla Olsson; Mustjoki, Satu; Stenke, Leif; Ekblom, Marja; Qian, Hong
Contributor: University of Helsinki, Medicum
Date: 2017-08-19
Language: eng
Number of pages: 7
Belongs to series: Biochemical and Biophysical Research Communications
ISSN: 0006-291X
URI: http://hdl.handle.net/10138/217891
Abstract: Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC. Based on these results, the 5-LO inhibitor zileuton has been introduced in clinical trials as a therapeutic option to target the LSC although its effect on primary human CML LSC has not been studied. We have here by using multiplex single cell PCR analyzed the expression of the mediators of the leukotriene pathway in bone marrow (BM) BCR-ABL(+)CD34(+)CD38(-) cells at diagnosis, and found low or undetectable expression of ALOX5. In line with this, zileuton did not exert significant overall growth inhibition in the long-term culture-initiating cell (LTC-IC) and colony (CFU-C) assays of BM CD34(+)CD38(-) cells from 7 CML patients. The majority of the single leukemic BCR-ABL(+)CD34(+)CD38(-) cells expressed cysteinyl leukotriene receptors CYSLTI and CYSLT2. However, montelukast, an inhibitor of CYSLTI, also failed to significantly suppress CFU-C and LTC-IC growth. These findings indicate that targeting ALOX5 or CYSLTI signaling with leukotriene antagonists, introduced into the clinical practice primarily as prophylaxis and treatment for asthma, may not be a promising pharmacological strategy to eradicate persisting LSC in CML patients. (C) 2017 The Author(s). Published by Elsevier Inc.
Subject: Leukotriene
Leukemic stem cells
Chronic myeloid leukemia
LTC-IC
IMATINIB MESYLATE TREATMENT
C-4 SYNTHASE
BONE-MARROW
EXPRESSION
CYSLT1
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
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