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

Stem Cell Reports
Ignazia TusaPersio Dello Sbarba

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.

Citations

Sep 12, 2020·Biochemical Society Transactions·Simon J CookPamela A Lochhead
Mar 25, 2019·International Journal of Molecular Sciences·Barbara Stecca, Elisabetta Rovida
Oct 18, 2020·Experimental & Molecular Medicine·Chun Shik Park, H Daniel Lacorazza
Mar 18, 2021·European Journal of Medicinal Chemistry·Seungbeom LeeHwayoung Yun
Aug 10, 2021·World Journal of Gastroenterology : WJG·Matias Estaras, Antonio Gonzalez

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Methods Mentioned

BETA
flow cytometry
Assay

Software Mentioned

GraphPad Prism

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