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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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; Gelali, Eleni; Johansson, Anne Sofie; Klang, Johannis; Xiao, Pingnan; Yektaei-Karin, Elham; Strömberg, Ulla Olsson; Mustjoki, Satu; Stenke, Leif; Ekblom, Marja; Qian, Hong.

In: Biochemical and Biophysical Research Communications, Vol. 490, No. 2, 08.2017, p. 378-384.

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Dolinska, M, Piccini, A, Wong, WM, Gelali, E, Johansson, AS, Klang, J, Xiao, P, Yektaei-Karin, E, Strömberg, UO, 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

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Dolinska, Monika ; Piccini, Alexandre ; Wong, Wan Man ; Gelali, Eleni ; Johansson, Anne Sofie ; Klang, Johannis ; Xiao, Pingnan ; Yektaei-Karin, Elham ; Strömberg, Ulla Olsson ; Mustjoki, Satu ; Stenke, Leif ; Ekblom, Marja ; Qian, Hong. / 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. In: Biochemical and Biophysical Research Communications. 2017 ; Vol. 490, No. 2. pp. 378-384.

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TY - JOUR

T1 - 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

AU - Dolinska, Monika

AU - Piccini, Alexandre

AU - Wong, Wan Man

AU - Gelali, Eleni

AU - Johansson, Anne Sofie

AU - Klang, Johannis

AU - Xiao, Pingnan

AU - Yektaei-Karin, Elham

AU - Strömberg, Ulla Olsson

AU - Mustjoki, Satu

AU - Stenke, Leif

AU - Ekblom, Marja

AU - Qian, Hong

PY - 2017/8

Y1 - 2017/8

N2 - 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.

AB - 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.

KW - Chronic myeloid leukemia

KW - Leukemic stem cells

KW - Leukotriene

KW - LTC-IC

U2 - 10.1016/j.bbrc.2017.06.051

DO - 10.1016/j.bbrc.2017.06.051

M3 - Article

VL - 490

SP - 378

EP - 384

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 1090-2104

IS - 2

ER -