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Leukotriene signali...
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, Monika (author)
- Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden.
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- Piccini, Alexandre (author)
- Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden.
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- Wong, Wan Man (author)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Lund Univ, Dept Lab Med, Lund, Sweden.
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- Gelali, Eleni (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden.
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- Johansson, Anne Sofie (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden.
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- Klang, Johannis (author)
- Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden.
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- Xiao, Pingnan (author)
- Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden.
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- Yektaei-Karin, Elham (author)
- Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden.
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- Strömberg, Ulla Ohlsson (author)
- Uppsala universitet,Hematologi,Uppsala University Hospital
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- Mustjoki, Satu (author)
- Helsinki University Central Hospital,University of Helsinki,Univ Helsinki, Dept Clin Chem & Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland.
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- Stenke, Leif (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden.
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- Ekblom, Marja (author)
- Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,Lund Univ, Dept Lab Med, Lund, Sweden.
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- Qian, Hong (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital,Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden.
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(creator_code:org_t)
- Elsevier BV, 2017
- 2017
- English.
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 490:2, s. 378-384
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Keyword
- Chronic myeloid leukemia
- Leukemic stem cells
- Leukotriene
- LTC-IC
- Leukotriene
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Dolinska, Monika
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Piccini, Alexand ...
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Wong, Wan Man
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Gelali, Eleni
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Johansson, Anne ...
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Klang, Johannis
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show more...
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Xiao, Pingnan
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Yektaei-Karin, E ...
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Strömberg, Ulla ...
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Mustjoki, Satu
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Stenke, Leif
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Ekblom, Marja
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Qian, Hong
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Biochemical and ...
- By the university
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Lund University
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Uppsala University
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Karolinska Institutet