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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

Dolinska, Monika; Piccini, Alexandre; Wong, Wan Man LU ; Gelali, Eleni; Johansson, Anne Sofie; Klang, Johannis; Xiao, Pingnan; Yektaei-Karin, Elham; Strömberg, Ulla Olsson and Mustjoki, Satu, et al. (2017) In Biochemical and Biophysical Research Communications
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... (More)

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.

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publication status
epub
subject
keywords
Chronic myeloid leukemia, Leukemic stem cells, Leukotriene, LTC-IC
in
Biochemical and Biophysical Research Communications
publisher
Elsevier
external identifiers
  • scopus:85020770907
  • wos:000406646600046
ISSN
0006-291X
DOI
10.1016/j.bbrc.2017.06.051
language
English
LU publication?
yes
id
46ce258a-8872-4b25-b3b3-0274317595c8
date added to LUP
2017-07-04 11:06:11
date last changed
2017-09-18 11:37:40
@article{46ce258a-8872-4b25-b3b3-0274317595c8,
  abstract     = {<p>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<sup>+</sup>CD34<sup>+</sup>CD38<sup>-</sup> 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<sup>+</sup>CD38<sup>-</sup> cells from 7 CML patients. The majority of the single leukemic BCR-ABL <sup>+</sup>CD34<sup>+</sup>CD38<sup>-</sup> 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.</p>},
  author       = {Dolinska, Monika and Piccini, Alexandre and Wong, Wan Man and Gelali, Eleni and Johansson, Anne Sofie and Klang, Johannis and Xiao, Pingnan and Yektaei-Karin, Elham and Strömberg, Ulla Olsson and Mustjoki, Satu and Stenke, Leif and Ekblom, Marja and Qian, Hong},
  issn         = {0006-291X},
  keyword      = {Chronic myeloid leukemia,Leukemic stem cells,Leukotriene,LTC-IC},
  language     = {eng},
  month        = {06},
  publisher    = {Elsevier},
  series       = {Biochemical and Biophysical Research Communications},
  title        = {Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34<sup>+</sup>CD38<sup>-</sup> stem and progenitor cells in chronic myeloid leukemia},
  url          = {http://dx.doi.org/10.1016/j.bbrc.2017.06.051},
  year         = {2017},
}