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

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2018 Sep 25

PMID 30245209

Citations 12

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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