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

Takeuchi, Miki; Kimura, Shinya; Kuroda, Junya; Ashihara, Eishi; Kawatani, Masahito; Osada, Hiroyuki; Umezawa, Kazuo; Yasui, Eiko; Imoto, Masaya; Tsuruo, Takashi; Yokota, Asumi; Tanaka, Ray; Nagao, Rina; Nakahata, Tatsutoshi; Fujiyama, Yoshihide; Maekawa, Taira

doi:10.1038/cdd.2010.6

Cited by 38 publications

(45 citation statements)

References 43 publications

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“…We found that even under prolonged treatments (96 hours), hypoxia alone does not reduce the levels of pCrkL in both stem and committed progenitors (Figure 2). This is in contrast to previous reports that in CML cell lines, hypoxia reduces the level of BCR-ABL1 phosphorylation 29 or BCR-ABL1 protein. 30 The reason behind this discrepancy is unclear, but it may be a result of differences in model systems between CML cell lines and primary human CML cells.…”

Section: Discussioncontrasting

confidence: 99%

“…26 Although hypoxia is emerging as a key factor in the biology of leukemia, 27 its role in CML LSCs and therapy resistance has not been thoroughly investigated. Although earlier studies have demonstrated that primary CML cells and CML cell lines can survive hypoxic conditions in vitro, [28][29][30] and that hypoxia confers both stem-like characteristics and imatinib resistance in cell lines, 29,30 it is unclear whether such features extend to primary CML LSCs.…”

Section: Introductionmentioning

confidence: 99%

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Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition

Manjeri

Lee

et al. 2014

Blood

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• Hypoxia mediates TKI resistance.• Hypoxia enhances CML stem cell maintenance.C-abl oncogene 1, nonreceptor tyrosine kinase (ABL1) kinase inhibitors such as imatinib mesylate (imatinib) are effective in managing chronic myeloid leukemia (CML) but incapable of eliminating leukemia stem cells (LSCs), suggesting that kinase-independent pathways support LSC survival. Given that the bone marrow (BM) hypoxic microenvironment supports hematopoietic stem cells, we investigated whether hypoxia similarly contributes to LSC persistence. Importantly, we found that although breakpoint cluster region (BCR)-ABL1 kinase remained effectively inhibited by imatinib under hypoxia, apoptosis became partially suppressed. Furthermore, hypoxia enhanced the clonogenicity of CML cells, as well as their efficiency in repopulating immunodeficient mice, both in the presence and absence of imatinib. Hypoxia-inducible factor 1 a (HIF1-a), which is the master regulator of the hypoxia transcriptional response, is expressed in the BM specimens of CML individuals. In vitro, HIF1-a is stabilized during hypoxia, and its expression and transcriptional activity can be partially attenuated by concurrent imatinib treatment. Expression analysis demonstrates at the whole-transcriptome level that hypoxia and imatinib regulate distinct subsets of genes. Functionally, knockdown of HIF1-a abolished the enhanced clonogenicity during hypoxia. Taken together, our results suggest that in the hypoxic microenvironment, HIF1-a signaling supports LSC persistence independent of BCR-ABL1 kinase activity. Thus, targeting HIF1-a and its pathway components may be therapeutically important for the complete eradication of LSCs. (Blood. 2014;123(21):3316-3326)

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition

Manjeri

Lee

et al. 2014

Blood

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“…The former include Bcr-Abl-related mechanisms, such as point mutations in the Abl kinase domain, and a variety of molecular abnormalities unrelated to Bcr-Abl (3)(4)(5)(6)(7)(8)(9). The latter include support of the bone marrow (BM) microenvironment (BMME), the so-called leukemia niche, which consists of soluble factors and supporting tissues, such as BM stromal cells (BMSCs), extracellular matrix (ECM), or hypoxia (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Various new agents have been proposed for overcoming cell-intrinsic mechanisms for drug resistance (20,21), and the precise molecular mechanisms for CML cell protection and maintenance by BMME sanctuary are not yet fully understood.…”

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confidence: 99%

Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia

Yamamoto-Sugitani

Kuroda

Ashihara

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Bone marrow (BM) microenvironment (BMME) constitutes the sanctuary for leukemic cells. In this study, we investigated the molecular mechanisms for BMME-mediated drug resistance and BM lodgment in chronic myelogenous leukemia (CML). Gene-expression profile as well as signal pathway and protein analyses revealed that galectin-3 (Gal-3), a member of the β-gal–binding galectin family of proteins, was specifically induced by coculture with HS-5 cells, a BM stroma cell-derived cell line, in all five CML cell lines examined. It was also found that primary CML cells expressed high levels of Gal-3 in BM. Enforced expression of Gal-3 activated Akt and Erk, induced accumulation of Mcl-1, and promoted in vitro cell proliferation, multidrug resistance to tyrosine kinase inhibitors for Bcr-Abl and genotoxic agents as a result of impaired apoptosis induction, and chemotactic cell migration to HS-5–derived soluble factors in CML cell lines independently of Bcr-Abl tyrosine kinase. The conditioned medium from Gal-3–overexpressing CML cells promoted in vitro cell proliferation of CML cells and HS-5 cells more than did the conditioned medium from parental cells. Moreover, the in vivo study in a mice transplantation model showed that Gal-3 overexpression promoted the long-term BM lodgment of CML cells. These results demonstrate that leukemia microenvironment-specific Gal-3 expression supports molecular signaling pathways for disease maintenance in BM and resistance to therapy in CML. They also suggest that Gal-3 may be a candidate therapeutic target to help overcome BMME-mediated therapeutic resistance.

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“…Blank et al did not investigate copy number change at the Glo1. Glo1 had increased expression in hypoxia-adapted tumour cell lines but copy number was not investigated as a possible mediating factor [48].…”

Section: Discussionmentioning

confidence: 99%

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

Shafie

Xue

Barker

et al. 2016

Biochemical Journal

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Glyoxalase 1 (Glo1) is a cytoplasmic enzyme with a cytoprotective function linked to metabolism of the cytotoxic side product of glycolysis, methylglyoxal (MG). It prevents dicarbonyl stress — the abnormal accumulation of reactive dicarbonyl metabolites, increasing protein and DNA damage. Increased Glo1 expression delays ageing and suppresses carcinogenesis, insulin resistance, cardiovascular disease and vascular complications of diabetes and renal failure. Surprisingly, gene trapping by the International Mouse Knockout Consortium (IMKC) to generate putative Glo1 knockout mice produced a mouse line with the phenotype characterised as normal and healthy. Here, we show that gene trapping mutation was successful, but the presence of Glo1 gene duplication, probably in the embryonic stem cells (ESCs) before gene trapping, maintained wild-type levels of Glo1 expression and activity and sustained the healthy phenotype. In further investigation of the consequences of dicarbonyl stress in ESCs, we found that prolonged exposure of mouse ESCs in culture to high concentrations of MG and/or hypoxia led to low-level increase in Glo1 copy number. In clinical translation, we found a high prevalence of low-level GLO1 copy number increase in renal failure where there is severe dicarbonyl stress. In conclusion, the IMKC Glo1 mutant mouse is not deficient in Glo1 expression through duplication of the Glo1 wild-type allele. Dicarbonyl stress and/or hypoxia induces low-level copy number alternation in ESCs. Similar processes may drive rare GLO1 duplication in health and disease.

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

Cited by 38 publications

References 43 publications

Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition

Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition

Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

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