期刊
HYPOXIA
卷 2, 期 -, 页码 1-10出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/HP.S51812
关键词
hypoxia; ischemia; chronic myeloid leukemia; stem cell niche; leukemia stem cell; drug resistance
类别
资金
- Istituto Toscano Tumori (ITT)
- Istituto Superiore di Sanita (ISS) - national program Stem Cells [CS64]
- Ministero della Salute [RF-TOS-2008-1163728]
- Regione Toscana - Programma per la Ricerca in Materia di Salute
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG5220, IG13466]
- Federazione Italiana per la Ricerca sul Cancro (FIRC)
- Associazione Italiana per la Lotta contro le Leucemie e i Linfomi (AIL
- Sezione di Prato)
- Fondazione Oretta Bartolomei-Corsi
- Fondazione Cassa di Risparmio di Volterra
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.
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