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

Ignazia Tusa1, Giulia Cheloni1, Martina Poteti2

  • 1Department 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.

Stem Cell Reports
|September 25, 2018
PubMed

Insights

Targeting the MEK5/ERK5 pathway effectively reduces chronic myeloid leukemia (CML) cell growth and stem cell populations. This approach offers a promising alternative to tyrosine kinase inhibitors (TKIs) for CML stem cell eradication.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Tyrosine kinase inhibitors (TKIs) are standard CML treatment but fail to eliminate leukemia stem cells (LSCs), leading to relapse.
  • Leukemia stem cell maintenance is influenced by the bone marrow microenvironment, including low oxygen conditions.

Purpose of the Study:

  • To investigate the MEK5/ERK5 pathway as a potential therapeutic target for LSCs in chronic myeloid leukemia (CML).
  • To identify novel therapeutic strategies alternative to BCR/ABL targeting for CML stem cell suppression.

Main Methods:

  • Investigated the MEK5/ERK5 pathway in CML patient-derived cells and cell lines under low oxygen conditions.
  • Assessed the efficacy of MEK5/ERK5 inhibitors versus TKIs on CML cell growth in vitro and in vivo.
  • Evaluated effects on leukemia stem cell properties like culture repopulation ability (CRA) and long-term culture-initiating cells (LTC-ICs).

Main Results:

  • MEK5/ERK5 pathway inhibition significantly reduced CML cell growth in vitro and in vivo.
  • MEK5/ERK5 inhibitors, unlike TKIs, markedly reduced CRA, serial colony formation, LTC-ICs, and CD26+ cells in CML samples.
  • MEK5/ERK5 inhibition demonstrated efficacy against CML cells irrespective of imatinib resistance and spared normal hematopoietic stem cells.

Conclusions:

  • The MEK5/ERK5 pathway is crucial for maintaining CML stem cells, particularly in the stem cell niche.
  • Targeting the MEK5/ERK5 pathway presents a novel and effective therapeutic strategy for eradicating CML progenitor and stem cells.
  • This approach may overcome TKI resistance and reduce CML relapse rates.
Keywords:
CMLERK5/MAPKMAP2K5MAPK7combination therapyhypoxialeukemia stem cellsmicroenvironmentstem cell nichetyrosine kinase inhibitors/TKi

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