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

Research output: Contribution to journalArticle

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 CYSLT1 and CYSLT2. However, montelukast, an inhibitor of CYSLT1, also failed to significantly suppress CFU-C and LTC-IC growth. These findings indicate that targeting ALOX5 or CYSLT1 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.

Details

Authors
  • Monika Dolinska
  • Alexandre Piccini
  • Wan Man Wong
  • Eleni Gelali
  • Anne Sofie Johansson
  • Johannis Klang
  • Pingnan Xiao
  • Elham Yektaei-Karin
  • Ulla Olsson Strömberg
  • Satu Mustjoki
  • Leif Stenke
  • Marja Ekblom
  • Hong Qian
Organisations
External organisations
  • Karolinska University Hospital
  • Karolinska Institutet
  • Uppsala University Hospital
  • Helsinki University Central Hospital
  • University of Helsinki
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Hematology

Keywords

  • Chronic myeloid leukemia, Leukemic stem cells, Leukotriene, LTC-IC
Original languageEnglish
Pages (from-to)378-384
JournalBiochemical and Biophysical Research Communications
Volume490
Issue number2
Early online date2017 Jun 13
Publication statusPublished - 2017 Aug
Publication categoryResearch
Peer-reviewedYes