Tyrosine kinase inhibitors (TKi) are effective against chronic myeloid leukemia (CML), but their inefficacy on leukemia stem cells (LSCs) may lead to relapse. To identify new druggable targets alternative to BCR/ABL, we investigated the role of the MEK5/ERK5 pathway in LSC maintenance in low oxygen, a feature of bone marrow stem cell niches. We found that MEK5/ERK5 pathway inhibition reduced the growth of CML patient-derived cells and cell lines in vitro and the number of leukemic cells in vivo. Treatment in vitro of primary CML cells with MEK5/ERK5 inhibitors, but not TKi, strikingly reduced culture repopulation ability (CRA), serial colony formation ability, long-term culture-initiating cells (LTC-ICs), and CD26-expressing cells. Importantly, MEK5/ERK5 inhibition was effective on CML cells regardless of the presence or absence of imatinib, and did not reduce CRA or LTC-ICs of normal CD34+ cells. Thus, targeting MEK/ERK5 may represent an innovative therapeutic approach to suppress CML progenitor/stem cells.

Targeting the Extracellular Signal-Regulated Kinase 5 Pathway to Suppress Human Chronic Myeloid Leukemia Stem Cells / Ignazia Tusa,Giulia Cheloni, Martina Poteti, Antonella Gozzini, Ngoc Ho DeSouza, Yi Shan, Xianming Deng, Nathanael S. Gray, Shaoguang Li, Elisabetta Rovida, Persio Dello Sbarba. - In: STEM CELL REPORTS. - ISSN 2213-6711. - STAMPA. - 11:(2018), pp. 929-943. [10.1016/j.stemcr.2018.08.016]

Targeting the Extracellular Signal-Regulated Kinase 5 Pathway to Suppress Human Chronic Myeloid Leukemia Stem Cells

Ignazia Tusa
Investigation
;
Giulia Cheloni
Investigation
;
Martina Poteti
Investigation
;
Antonella Gozzini;Elisabetta Rovida
Conceptualization
;
Persio Dello Sbarba
Writing – Review & Editing
2018

Abstract

Tyrosine kinase inhibitors (TKi) are effective against chronic myeloid leukemia (CML), but their inefficacy on leukemia stem cells (LSCs) may lead to relapse. To identify new druggable targets alternative to BCR/ABL, we investigated the role of the MEK5/ERK5 pathway in LSC maintenance in low oxygen, a feature of bone marrow stem cell niches. We found that MEK5/ERK5 pathway inhibition reduced the growth of CML patient-derived cells and cell lines in vitro and the number of leukemic cells in vivo. Treatment in vitro of primary CML cells with MEK5/ERK5 inhibitors, but not TKi, strikingly reduced culture repopulation ability (CRA), serial colony formation ability, long-term culture-initiating cells (LTC-ICs), and CD26-expressing cells. Importantly, MEK5/ERK5 inhibition was effective on CML cells regardless of the presence or absence of imatinib, and did not reduce CRA or LTC-ICs of normal CD34+ cells. Thus, targeting MEK/ERK5 may represent an innovative therapeutic approach to suppress CML progenitor/stem cells.
2018
11
929
943
Ignazia Tusa,Giulia Cheloni, Martina Poteti, Antonella Gozzini, Ngoc Ho DeSouza, Yi Shan, Xianming Deng, Nathanael S. Gray, Shaoguang Li, Elisabetta Rovida, Persio Dello Sbarba
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1137387
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