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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
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
Lund Univ, Dept Lab Med, Lund, Sweden..
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
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2017 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 490, no 2, p. 378-384Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2017. Vol. 490, no 2, p. 378-384
Keyword [en]
Leukotriene, Leukemic stem cells, Chronic myeloid leukemia, LTC-IC
National Category
Hematology
Identifiers
URN: urn:nbn:se:uu:diva-334034DOI: 10.1016/j.bbrc.2017.06.051ISI: 000406646600046PubMedID: 28623130OAI: oai:DiVA.org:uu-334034DiVA, id: diva2:1159694
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-11-23Bibliographically approved

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