One More Stem Cell Niche: How the Sensitivity of Chronic Myeloid Leukemia Cells to Imatinib Mesylate is Modulated Within a "hypoxic" Environment

Overview

Journal Hypoxia (Auckl)

Publisher Dove Medical Press

Date 2014 Jan 21

PMID 27774462

Citations 13

Authors

Elisabetta Rovida

Ilaria Marzi

Maria Grazia Cipolleschi

Persio Dello Sbarba

Affiliations

Soon will be listed here.

Abstract

This is a review (by no means comprehensive) of how the stem cell niche evolved from an abstract concept to a complex system, implemented with a number of experimental data at the cellular and molecular levels, including metabolic cues, on which we focused in particular. The concept was introduced in 1978 to model bone marrow sites suited to host hematopoietic stem cells (HSCs) and favor their self-renewal, while restraining clonal expansion and commitment to differentiation. Studies of the effects of low oxygen tension on HSC maintenance in vitro led us to hypothesize niches were located within bone marrow areas where oxygen tension is lower than elsewhere. We named these areas hypoxic stem cell niches, although a low oxygen tension is to be considered physiological for the environment where HSCs are maintained. HSCs were later shown to have the option of cycling in low oxygen, which steers this cycling to the maintenance of stem cell potential. Cell subsets capable of withstanding incubation in very low oxygen were also detected within leukemia cell populations, including chronic myeloid leukemia (CML). The oncogenetic Bcr/Abl protein is completely suppressed in these subsets, whereas Bcr/Abl messenger ribonucleic acid is not, indicating that CML cells resistant to low oxygen are independent of Bcr/Abl for persistence in culture but remain genetically leukemic. Accordingly, leukemia stem cells of CML selected in low oxygen are refractory to the Bcr/Abl inhibitor imatinib mesylate. Bcr/Abl protein suppression turned out to be actually determined when glucose shortage complicated the effects of low oxygen, indicating that ischemia-like conditions are the driving force of leukemia stem cell refractoriness to imatinib mesylate. These studies pointed to "ischemic" stem cell niches as a novel scenario for the maintenance of minimal residual disease of CML. A possible functional relationship of the "ischemic" with the "hypoxic" stem cell niche is discussed.

Citing Articles

Liquid biopsies and minimal residual disease in lymphoid malignancies.

Zerdan M, Kassab J, Saba L, Haroun E, Zerdan M, Allam S Front Oncol. 2023; 13:1173701.

PMID: 37228488 PMC: 10203459. DOI: 10.3389/fonc.2023.1173701.

Closer to Nature: The Role of MSCs in Recreating the Microenvironment of the Hematopoietic Stem Cell Niche in vitro.

Wuchter P, Diehlmann A, Kluter H Transfus Med Hemother. 2022; 49(4):258-267.

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Glutamine Availability Controls BCR/Abl Protein Expression and Functional Phenotype of Chronic Myeloid Leukemia Cells Endowed with Stem/Progenitor Cell Potential.

Poteti M, Menegazzi G, Peppicelli S, Tusa I, Cheloni G, Silvano A Cancers (Basel). 2021; 13(17).

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Molecular Testing in CML between Old and New Methods: Are We at a Turning Point?.

Soverini S, Bernardi S, Galimberti S J Clin Med. 2020; 9(12).

PMID: 33261150 PMC: 7760306. DOI: 10.3390/jcm9123865.

Normal Hematopoetic Stem and Progenitor Cells Can Exhibit Metabolic Flexibility Similar to Cancer Cells.

Vlaski-Lafarge M, Labat V, Brandy A, Refeyton A, Duchez P, Rodriguez L Front Oncol. 2020; 10:713.

PMID: 32528878 PMC: 7247845. DOI: 10.3389/fonc.2020.00713.

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