Severe Hypoxia Defines Heterogeneity and Selects Highly Immature Progenitors Within Clonal Erythroleukemia Cells

Giuntoli, Serena; Rovida, Elisabetta; Gozzini, Antonella; Barbetti, Valentina; Cipolleschi, Maria Grazia; Olivotto, Massimo; Sbarba, Persio Dello

doi:10.1634/stemcells.2006-0637

Cited by 45 publications

(58 citation statements)

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“…Previously, investigators have studied the role of hypoxia in leukemia using relatively shortterm assays. [30][31][32] Our results suggest that transient hypoxia may not adequately mimic the physiological environment of CML cells (Figure 3e). Furthermore, in the mouse CML xenograft model, the oxygen concentration of engrafted leukemic cells in the BM was o10 mm Hg (B1.3% O 2 ) (Figure 1f).…”

Section: Discussionmentioning

confidence: 92%

“…Giuntoli et al 32 have also reported that the hypoxic selection of CML cells resulted in decreased cell sensitivity to imatinib and activation of Bcr-Abl-independent survival signaling pathways. Erk, a downstream effector of Bcr-Abl, was also less phosphorylated in HA-CML cells compared with parental cells, whereas the levels of p-Akt and p-Stat5 were similar (Figure 2f).…”

Section: Discussionmentioning

confidence: 97%

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Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

et al. 2010

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Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl þ leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl þ stem cells is needed to cure leukemias caused by Bcr-Abl þ cells. Human Bcr-Abl þ cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl þ sublines by selection in long-term hypoxic cultures (1.0% O 2 ). Interestingly, HA-Bcr-Abl þ cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher b-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl þ cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl þ cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl þ leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl þ leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

et al. 2010

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“…1,2 The existence of different, metabolically characterized, functional cell subsets within leukemia cell populations reflects the organization of normal hematopoiesis, where the regulatory role of glycolysis and respiration within the stem/progenitor cell hierarchy has been long known. [3][4][5][6] Such an organization is functional to the maintenance of stem cells within restricted, "metabolically-defined" bone marrow areas which we called the "hypoxic stem cell niches".…”

Section: Introductionmentioning

confidence: 99%

Glucose availability in hypoxia regulates the selection of chronic myeloid leukemia progenitor subsets with different resistance to imatinib-mesylate

Giuntoli¹,

Tanturli²,

Gesualdo³

et al. 2010

Haematologica

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BackgroundIncubation of chronic myeloid leukemia cells in hypoxia inhibits growth and selects BCR/Ablindependent cells with stem cell properties which are refractory to imatinib-mesylate. This study aimed to characterize the relationship of this refractoriness with glucose availability in the environment. Design and MethodsK562 or primary chronic myeloid leukemia cells were cultured at 0.1% O2, different cell densities and glucose concentrations. The stem and progenitor cell potential of these cultures at different times of incubation in relation to BCR/Ablprotein expression and sensitivity to imatinibmesylate was explored by transferring cells to growth-permissive secondary cultures in normoxia, according to the Culture-Repopulating Ability assay methodology. ResultsHypoxia-resistant cells maintained BCR/Ablprotein expression until glucose was no longer available in primary hypoxic cultures, where glucose availability appeared to regulate cell number and the balance between the enrichment of cells with kinetic properties typical of stem or progenitor cells. Cells surviving merely hypoxic conditions were, upon transfer to secondary cultures, immediately available for numerical expansion due to the maintained BCR/Ablprotein expression, and were consequently sensitive to imatinib-mesylate. Instead, BCR/Ablprotein-negative cells selected in primary cultures under oxygen/glucose shortage underwent a delayed numerical expansion in secondary cultures, which was completely refractory to imatinib-mesylate. Cells with the latter properties were also found in primary chronic myeloid leukemia explants. ConclusionsGlucose shortage in hypoxia was shown to represent the condition selecting BCR/Ablprotein-negative cells refractory to imatinib-mesylate from either chronic myeloid leukemia lines or patients. These cells, exhibiting stem cell properties in vitro, are metabolically suited to home to stem cell niches in vivo and so may represent the chronic myeloid leukemia cell subset responsible for minimal residual disease.Key words: imatinib-mesylate, chronic myeloid leukemia, glucose, hypoxia.Citation: Giuntoli S, Tanturli M, Di Gesualdo F, Barbetti V, Rovida E, and Dello Sbarba P. Glucose availability in hypoxia regulates the selection of chronic myeloid leukemia progenitor subsets with different resistance to imatinib-mesylate. Haematologica 2011;96(2):204-212. doi:10.3324/haematol.2010 Glucose availability in hypoxia regulates the selection of chronic myeloid leukemia progenitor subsets with different resistance to imatinib-mesylate

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“…These results suggested that a compromised blood flow with very low oxygen support could favor the outgrowth and survival of AML clones reducing their exposure to systemic chemotherapy and immune effector cells [79]. This suggestion has been indirectly confirmed by the finding that leukemic cells requiring very low oxygen and energy support correspond to quiescent, chemoresistant and self-renewing leukemic cell subsets [82]. These functionally defined LSCs are completely dependent on mitochondrial respiration to fulfill their low energy requirements as they are unable to employ glycolysis [83].…”

Section: Niche Contribution To Aml Developmentmentioning

confidence: 80%

“…Various studies have demonstrated that LSCs and HSCs might share the same bone marrow niches [25,26,32] and compete for vacant niches as the number of these areas within the BM is limited [29]. Since these malignant niches provide a shelter for LSCs [79,82,83] and also specify their self-renewal properties [10,22,23] an attractive therapeutic strategy could be to dislodge these cells from their niche by targeting the CXCR4/CXCL12 interaction. Xenograft models have already shown that CXCR4-CXCL12 targeting is feasible and could lead to more efficient disease eradication [92,105]; these data have provided the rationale to combine Plerixafor (ADM3100), the principal manipulator of the CXCR4-CXCL12 axis, with conventional chemotherapy (Table II).…”

Section: Potential Targetsmentioning

confidence: 99%

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

et al. 2016

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A tight relationship between the acute myeloid leukemia (AML) population and the bone marrow (BM) microenvironment has been convincingly established. The AML clone contains leukemic stem cells (LSCs) that compete with normal hematopoietic stem cells (HSCs) for niche occupancy and remodel the niche; whereas, the BM microenvironment might promote AML development and progression not only through hypoxia and homing/adhesion molecules, but also through genetic defects. Although it is still unknown whether the niche influences treatment results or contains any potential target for treatment, this dynamic AML-niche interaction might be a promising therapeutic objective to significantly improve the AML cure rate.

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Severe Hypoxia Defines Heterogeneity and Selects Highly Immature Progenitors Within Clonal Erythroleukemia Cells

Abstract: We showed that resistance to severe hypoxia defines hierarchical levels within normal hematopoietic populations and that hypoxia modulates the balance between generation of progenitors and maintenance of hematopoietic stem cells (

Cited by 45 publications

References 20 publications

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

Glucose availability in hypoxia regulates the selection of chronic myeloid leukemia progenitor subsets with different resistance to imatinib-mesylate

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

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