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

Abstract

Summary: 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. : Tyrosine kinase inhibitors targeting BCR/ABL are very effective against chronic myeloid leukemia (CML) cells but not leukemia stem cells (LSCs). Dello Sbarba, Rovida, and colleagues discovered that targeting the extracellular signal-regulated kinase 5 pathway in CML cell lines and primary cells results in the suppression of LSC as well as, especially in combination with tyrosine kinase inhibitors, the overall cell population. Keywords: leukemia stem cells, ERK5/MAPK, combination therapy, hypoxia, CML, MAPK7, MAP2K5, tyrosine kinase inhibitors/TKi, microenvironment, stem cell niche