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

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

  • Stem Cell Reports. 2018 Oct 9;11(4):929-943. doi: 10.1016/j.stemcr.2018.08.016.
Ignazia Tusa 1,  Giulia Cheloni 1,  Martina Poteti 2,  Antonella Gozzini 3,  Ngoc Ho DeSouza 4,  Yi Shan 4,  Xianming Deng 5,  Nathanael S Gray 5,  Shaoguang Li 4,  Elisabetta Rovida 6,  Persio Dello Sbarba 7
Affiliations

Affiliations

  • 1 Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, viale G.B. Morgagni, 50, Firenze 50134, Italy; Istituto Toscano Tumori (ITT), Firenze 50134, Italy.
  • 2 Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, viale G.B. Morgagni, 50, Firenze 50134, Italy.
  • 3 Hematology Unit, Careggi University Hospital (AOUC), Firenze 50134, Italy.
  • 4 Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA.
  • 5 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 6 Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, viale G.B. Morgagni, 50, Firenze 50134, Italy; Istituto Toscano Tumori (ITT), Firenze 50134, Italy. Electronic address: [email protected].
  • 7 Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, viale G.B. Morgagni, 50, Firenze 50134, Italy; Istituto Toscano Tumori (ITT), Firenze 50134, Italy. Electronic address: [email protected].
PMID: 30245209 DOI: 10.1016/j.stemcr.2018.08.016
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.

Keywords

CML; ERK5/MAPK; MAP2K5; MAPK7; combination therapy; hypoxia; leukemia stem cells; microenvironment; stem cell niche; tyrosine kinase inhibitors/TKi.

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