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

Abstract

SummaryTyrosine 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.

In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features

“…3a). CD26 was expressed at high levels in KCL22, but not in K562 and LAMA-84 cells, as previously reported by us and others [13,62] (Fig. 3a).…”

“…This conclusion is further supported by the finding that the progressive fading off of TKi effect was paralleled by the consistent effectiveness of XMD8-92, which we previously showed to exhibit an enhanced inhibitory action on the relatively more immature CML cells and on the maintenance of the CML stem cell compartment. Besides providing interesting pieces of evidence with respect to the effect of imatinib versus ponatinib, our experiments indicated that serial CFA assays are adequate to test the effects of drugs on leukemia progenitor/stem cell subsets [8,9,12,13,38,73].…”

“…In this study, we compared the effects of TKi belonging to different generations, imatinib and ponatinib, on the expression of progenitor/stem cell markers and potential in both CML cell lines, taking advantage of our previous demonstration that leukemic cell lines contain cell subsets endowed with progenitor/stem cell properties [9,12,13,38,39], as well as patient-derived cells.…”

“…In order to evaluate functionally, rather than phenotypically, the effects of imatinib and ponatinib on CML progenitor/ stem cell potential, cells were subjected to serial CFA assay ( Fig. 6) [12,13]. Both drugs strikingly (KCL22, Fig.…”

Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…

“…Furthermore, knockout of ERK5 in keratinocytes prevents inflammation-driven tumorigenesis [30]. Knockdown of ERK5 (or MEK5) by siRNA has also shown the therapeutic potential of the ERK5 pathway in mutant BRAF-driven melanoma [31,32,33], mutant KRAS-driven pancreatic ductal adenocarcinoma (PDAC) [34], as well as prostate [35], breast [36] and bladder cancers [37]. There are conflicting results obtained with ERK5 siRNA in hepatocellular carcinoma (HCC) [38,39].…”