Targeting HIF1α Eliminates Cancer Stem Cells in Hematological Malignancies
Open accessAbstract
Molecular targeting of cancer stem cells (CSCs) has therapeutic potential for efficient treatment of cancer, although relatively few specific targets have been identified so far. Hypoxia-inducible factor (HIF) was recently shown to regulate the tumorigenic capacity of glioma stem cells under hypoxic conditions. Surprisingly, we found that, under normoxia, HIF1α signaling was selectively activated in the stem cells of mouse lymphoma and human acute myeloid leukemia (AML). HIF1a shRNA and HIF inhibitors abrogated the colony-forming unit (cfu) activity of mouse lymphoma and human AML CSCs. Importantly, the HIF-inhibitor echinomycin efficiently eradicated mouse lymphoma and serially transplantable human AML in xenogeneic models by preferential elimination of CSCs. Hif1α maintains mouse lymphoma CSCs by repressing a negative feedback loop in the Notch pathway. Taken together, our results demonstrate an essential function of Hif1α-Notch interaction in maintaining CSCs and provide an effective approach to target CSCs for therapy of hematological malignancies.
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Echinomycin dissolved in DMSO is active against leukemia in mice.
“We have demonstrated that echinomycin, dissolved in dimethyl sulfoxide (DMSO) is active against leukemia in mice24, 25.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [25]
The Results section, “Therapeutic elimination of leukemia stem cells (LSC) for AML,” reports that echinomycin eliminated or substantially reduced human leukemia in mice. The Experimental Procedures describe echinomycin injections but do not identify DMSO as the solvent; a search for DMSO found no supporting passage. Thus the activity in mice is supported, but the formulation is not. (LLM, conf=0.87)
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- Kong, 2005, Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity, Cancer Res., 65, 9047, 10.1158/0008-5472.CAN-05-1235 · DOI · Paper page
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Cancer stem cells and chemoresistance: The smartest survives the raid
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“renewal (73) and the clonogenecity of leukemic CSCs (60, 61).”
Noman, M. Z., Hasmim, M., Messai, Y., Terry, S., Kiéda, C., Janji, B., & Chouaı̈b, S. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00207.2015 · Cited by 405 · see citing works
“(116) using human acute lymphocytic leukemia showed a selective activation of HIF-1 in leukemia stem cells under normoxic conditions compared with the bulk of leukemia blasts.”
BackgroundKryczek, I., Lin, Y., Nagarsheth, N., Peng, D., Zhao, L., Zhao, E., Vatan, L., Szeliga, W., Dou, Y., Owens, S. R., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.03.010 · Cited by 389 · see citing works
“IL- 22 induced potent and equal sphere formation in colon cancer cells expressing vectors encoding: GFP (scramble), Notch active domain (Notch-IC), and Notch-negative domain (Notch-DN) (Wang et al., 2011; Yamamoto et al., 2001) (Figure S3C).”
BackgroundInfluentialFrom Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling
Ntziachristos, P., Lim, J. S., Sage, J., & Aifantis, I. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.018 · Cited by 369 · see citing works
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BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation
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Regulatory Mechanisms of Tumor Suppressor P16INK4Aand Their Relevance to Cancer
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Human T <sub>H</sub> 17 Cells Are Long-Lived Effector Memory Cells
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Pharmacologic Targeting of Hypoxia-Inducible Factors
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DawnRank: discovering personalized driver genes in cancer
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Cancer stem cells (CSCs): metabolic strategies for their identification and eradication
Francesco, E. M. D., Sotgia, F., & Lisanti, M. P. (2018) · Biochemical Journal · doi:10.1042/bcj20170164 · Cited by 268 · see citing works
Microenvironment and tumor cell plasticity: An easy way out
Taddei, M. L., Giannoni, E., Comito, G., & Chiarugi, P. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.01.042 · Cited by 263 · see citing works
HIF-1 in cancer therapy: two decade long story of a transcription factor
Soni, S., & Padwad, Y. S. (2017) · Acta Oncologica · doi:10.1080/0284186x.2017.1301680 · Cited by 251 · see citing works
Cancer stem cells: In the line of fire
Alison, M. R., Lin, W., Lim, S. M. L., & Nicholson, L. J. (2012) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2012.03.003 · Cited by 222 · see citing works
“Using a Wee-1 kinase inhibitor, it was possible to sensitise glioblastoma cells to irradiation.31 A number of other pathways have been implicated in the radioresistance of brain CSCs.”
BackgroundInfluentialLópez de Andrés, J., Griñán-Lisón, C., Jiménez, G., & Marchal, J. A. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00966-3 · Cited by 207 · see citing works
Schwab, L. P., Peacock, D. L., Majumdar, D., Ingels, J. F., Jensen, L. C., Smith, K., Cushing, R. C., & Seagroves, T. N. (2012) · Breast Cancer Research · doi:10.1186/bcr3087 · Cited by 220 · see citing works
“The direct relationship of the hypoxic response to TIC activity has been demonstrated in adult glioma, human acute myeloid leukemia (AML) and murine lymphoma [15,16].”
BackgroundMethodResultInfluentialMathieu, J., Zhou, W., Xing, Y., Sperber, H., Ferreccio, A., Agoston, Z., Kuppusamy, K. T., Moon, R. T., & Ruohola‐Baker, H. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.02.012 · Cited by 209 · see citing works
“However, recent data indicate that HIF1a can also regulate stem cell properties (Takubo et al., 2010; Wang et al., 2011).”
BackgroundZhang, W. C., Chin, T. M., Yang, H. H., Nga, M. E., Lunny, D. P., Lim, E. K. H., Sun, L., Pang, Y. H., Leow, Y. N., Malusay, S. R. Y., et al. (2016) · Nature Communications · doi:10.1038/ncomms11702 · Cited by 201 · see citing works
“Mounting evidence has pointed to TICs as being crucial drivers of tumour initiation, growth, metastasis and resistance 4,5,55–57 , and one needs to ablate TICs in addition to treating bulk tumour cells 58–60 .”
The hypoxic microenvironment: A determinant of cancer stem cell evolution
Carnero, A., & LLeonart, M. E. (2016) · BioEssays · doi:10.1002/bies.201670911 · Cited by 201 · see citing works
Li, W., Li, F., Zhang, X., Lin, H., & Xu, C. S. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00825-8 · Cited by 203 · see citing works
HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells
Zhang, H., Li, H., Xi, H. S., & Li, S. (2012) · Blood · doi:10.1182/blood-2011-10-387381 · Cited by 192 · see citing works
Rouault‐Pierre, K., López-Onieva, L., Foster, K., Anjos‐Afonso, F., Lamrissi‐Garcia, I., Serrano-Sanchez, M., Mitter, R., Ivanović, Z., de Verneuil, H., Gribben, J. G., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.08.011 · Cited by 187 · see citing works
Ito, D., Frantz, A. M., & Modiano, J. F. (2014) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2014.02.016 · Cited by 182 · see citing works
“Howver, there are only a few reports supporting the existence f TICs in human lymphoma cell lines or in transgenic ymphoma mouse models (Lee et al., 2012; Vega et al., 009; Wang et al., 2011).”
Bao, B., Azmi, A. S., Ali, S. S., Ahmad, A., Li, Y., Banerjee, S., Kong, D., & Sarkar, F. H. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.04.008 · Cited by 180 · see citing works
“Conditional knock-down of HIF-1α attenuates the expansion of hypoxia-induced CD133+ CSCs, which are confirmed by other recent findings [155,156].”
ResultTumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities
Beckers, C., Pruschy, M. N., & Vetrugno, I. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.11.006 · Cited by 182 · see citing works
Hypoxia and Metabolic Properties of Hematopoietic Stem Cells
Zhang, C. C., & Sadek, H. A. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.5019 · Cited by 154 · see citing works
“In addition, the high level of Hif-1a expression maintained in acute myeloid leukemia stem cells is no longer dependent on a hypoxic environment (124).”
BackgroundBailey, C. M., Liu, Y., Liu, M., Du, X., Devenport, M., Zheng, P., Liu, Y., & Wang, Y. (2022) · Journal of Clinical Investigation · doi:10.1172/jci150846 · Cited by 151 · see citing works
“We have reported that echinomycin effectively eliminated leukemia stem cells (34).”
Self-citationROS-activated Anticancer Prodrugs: a New Strategy for tumor-specific Damage
Peng, X., & Gandhi, V. V. (2012) · Therapeutic Delivery · doi:10.4155/tde.12.61 · Cited by 147 · see citing works
Soda, Y., Myskiw, C., Rommel, A., & Verma, I. M. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1019-z · Cited by 141 · see citing works
“from hematological malignancies, HIF-1α supports CSC maintenance and tumorigenicity by suppressing a negative feedback loop in the Notch pathway [102].”
BackgroundMolecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy
Baran, N., & Konopleva, M. Y. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0895 · Cited by 138 · see citing works
Frolova, O., Samudio, I. J., Benito, J. M., Jacamo, R. O., Kornblau, S. M., Marković, A. K., Schober, W. D., Lu, H., Qiu, Y. H., Buglio, D., et al. (2012) · Cancer Biology & Therapy · doi:10.4161/cbt.20838 · Cited by 130 · see citing works
Hypoxia-inducible factors in cancer stem cells and inflammation
Peng, G., & Liu, Y. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.03.003 · Cited by 124 · see citing works
“Wang and colleagues used a syngeneic transplantation model to demonstrate that the cKit+Sca-1+ population in their mouse model of ALL are the leukemia initiating cells [9].”
InfluentialFarrugia, F., & Charalampopoulos, A. A. (2019) · Endocrine Regulations · doi:10.2478/enr-2019-0020 · Cited by 123 · see citing works
“In cancer, HIFs activate transcription of genes that play key roles in the critical aspects of cancer biology, including stem cell maintenance (Wang et al. 2011), cell immortalization, epithelial-mesenchymal transition (Mak et al. 2010), genetic instability (Huang et al. 2007), vascularization…”
BackgroundNontranscriptional Role of Hif-1α in Activation of γ-Secretase and Notch Signaling in Breast Cancer
Villa, J. C., Chiu, D., Brandes, A., Escorcia, F. E., Villa, C. H., Maguire, W. F., Hu, C., de Stanchina, E., Simon, M. C., Sisodia, S. S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.028 · Cited by 122 · see citing works
“Notch and hypoxia-inducible factor-1α (Hif-1α) signaling pathways control many essential biological processes, from stem cell development to organogenesis, and the cross-talk between both pathways has been investigated in several biological systems (Gustafsson et al., 2005; Mukherjee et al., 2011; Wang et al., 2011).”
InfluentialXiang, L., Gilkes, D. M., Hu, H., Takano, N., Luo, W., Lu, H., Bullen, J. W., Samanta, D., Liang, H., & Semenza, G. L. (2014) · Oncotarget · doi:10.18632/oncotarget.2997 · Cited by 119 · see citing works
“HIF transcriptional activity is constitutively increased in mouse lymphoma and human acute myeloid leukemia CSCs, which were eliminated by treatment with a HIF-1 inhibitor [14].”
BackgroundHypoxia and the phenomenon of immune exclusion
Pietrobon, V., & Marincola, F. M. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-020-02667-4 · Cited by 119 · see citing works
“HIF proteins activate the transcription of genes involved in stem cell maintenance [90], apoptosis, cell immortalization, epithelial to mesenchymal transition [91], genetic instability [92], erythropoiesis and angiogenesis [93], glycolysis [94], pH regulation [95], immune evasion [96], invasion and metastasis [97] and…”
BackgroundLeukemia stem cells in T-ALL require active Hif1α and Wnt signaling
Giambra, V., Jenkins, C. E., Lam, S. H. L., Hoofd, C., Belmonte, M., Wang, X., Gusscott, S., Gracias, D., & Weng, A. P. (2015) · Blood · doi:10.1182/blood-2014-10-609370 · Cited by 116 · see citing works
Griessinger, E., Anjos‐Afonso, F., Pizzitola, I., Rouault‐Pierre, K., Vargaftig, J., Taussig, D. C., Gribben, J. G., Lassailly, F., & Bonnet, D. A. (2014) · Stem Cells Translational Medicine · doi:10.5966/sctm.2013-0166 · Cited by 115 · see citing works
Schöning, J., Monteiro, M. J., & Gu, W. (2016) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12693 · Cited by 115 · see citing works
Oxidative stress and hypoxia in normal and leukemic stem cells
Testa, U., Labbaye, C., Castelli, G., & Pelosi, E. (2016) · Experimental Hematology · doi:10.1016/j.exphem.2016.04.012 · Cited by 112 · see citing works
Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy
Martínez‐Sáez, O., Borau, P. G., Alonso‐Gordoa, T., Molina‐Cerrillo, J., & Grande, E. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.01.013 · Cited by 109 · see citing works
“…HI Chetomin Inhibition of HIF transcriptional activity HI Bortezomib Inhibition of HIF transcriptional activity HI PT2385 HIF-2 PAS-B dimerization antagonism HI PT2399 HIF-2 PAS-B dimerization antagonism HI ology/Hematology 111 (2017) 117–123 119 HIF-1 DNA (Kong et al., 2005; Wang et al., 2011).”
BackgroundHypoxic Stress-Induced Tumor and Immune Plasticity, Suppression, and Impact on Tumor Heterogeneity
Terry, S., Buart, S., & Chouaı̈b, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01625 · Cited by 111 · see citing works
Hypoxia inducible factors in the tumor microenvironment as therapeutic targets of cancer stem cells
Hajizadeh, F., Okoye, I., Esmaily, M., Chaleshtari, M. G., Masjedi, A., Azizi, G., Irandoust, M., Ghalamfarsa, G., & Jadidi‐Niaragh, F. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116952 · Cited by 104 · see citing works
van Gils, N., Denkers, F., & Smit, L. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.659253 · Cited by 87 · see citing works
A hostel for the hostile: the bone marrow niche in hematologic neoplasms
Krause, D. S., & Scadden, D. T. (2015) · Haematologica · doi:10.3324/haematol.2014.113852 · Cited by 102 · see citing works
“Knockdown of HIF-1 α and the use of the HIF inhibitor echinomycin abrogated the colony-forming unit activity and eradicated LSC in human AML, as tested by serial transplantation assays in xenotransplants.(86) Deregulation of HIF-2 α, which impaired the long-term repopulating ability of human CD34 cells, impaired the e…”
Methodde Leeuw, D. C., Denkers, F., Olthof, M. C., Rutten, A. P., Pouwels, W., Schuurhuis, G. J., Ossenkoppele, G. J., & Smit, L. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-1733 · Cited by 101 · see citing works
HIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia
Velasco-Hernández, T., Wittsten, A. H., Rehn, M., Bryder, D., & Cammenga, J. (2014) · Blood · doi:10.1182/blood-2014-04-567065 · Cited by 101 · see citing works
“This dependence has been demonstrated using shRNA and inhibitors to block HIF-1/2a function, followed by transplantation into NOD/SCID/IL2Rg (NSG) mice.(20,21) However, genetic alterations of the AML samples used were not investigated, so it remains unclear whether the requirement for HIFs is dependent on signaling di…”
BackgroundMethodTafani, M., Pucci, B., Russo, A., Schito, L., Pellegrini, L., Perrone, G. A., Villanova, L., Salvatori, L., Ravenna, L., Petrangeli, E., et al. (2013) · Frontiers in Pharmacology · doi:10.3389/fphar.2013.00013 · Cited by 99 · see citing works
“Finally, echinomycin, an antibiotic isolated from Streptomyces echinatus, binds to DNA and inhibits HIF1α activity (Wang et al., 2011).”
BackgroundHypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer
Seo, E. J., Kim, D. K., Jang, I. H., Choi, E. J., Shin, S., Lee, S. I., Kwon, S., Kim, K., Suh, D., & Kim, J. H. (2016) · Oncotarget · doi:10.18632/oncotarget.10954 · Cited by 99 · see citing works
Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition
Ng, K. P., Manjeri, A., Lee, K. L., Huang, W., Tan, S., Chuah, C. T. H., Poellinger, L., & Ong, S. T. (2014) · Blood · doi:10.1182/blood-2013-07-511907 · Cited by 96 · see citing works
“The cellular hypoxic response is primarily driven by HIFs, and both HIF1−α and HIF-2a play key roles in cancer stem cells.(37) 38 We therefore sought to analyze HIF expression in CML BM from patients in CP and BC using immunohistochemistry.”
BackgroundHypoxia, notch signalling, and prostate cancer
Marignol, L. H., Rivera-Figueroa, K., Lynch, T. H., & Hollywood, D. P. (2013) · Nature Reviews Urology · doi:10.1038/nrurol.2013.110 · Cited by 95 · see citing works
Chen, S., Huang, J., Liu, Z., Liang, Q., Zhang, N., & Jin, Y. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.3 · Cited by 93 · see citing works
Das, B., Pal, B., Bhuyan, R., Li, H., Sarma, A., Gayan, S., Talukdar, J., Sandhya, S., Bhuyan, S., Gogoi, G., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2847 · Cited by 92 · see citing works
“Additionally, gene products that can confer self-renewal in cancer have been identified including the iPS gene products MYC, Nanog, Sox2, Oct-4, as well as hypoxia-inducible factors (HIFs) (11-23).”
BackgroundDynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors
Semenza, G. L. (2015) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2015.09.004 · Cited by 92 · see citing works
Chetomin, targeting HIF-1α/p300 complex, exhibits antitumour activity in multiple myeloma
Viziteu, E., Grandmougin, C., Goldschmidt, H., Seckinger, A., Hose, D., Klein, B., & Moreaux, J. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.20 · Cited by 93 · see citing works
“Furthermore, HIF-1a represents an interesting target to eradicate cancer stem cells in haematological malignancies including lymphoma and acute myeloid leukemia (Wang et al, 2011).”
BackgroundMetastatic cancer stem cells: from the concept to therapeutics.
Liao, W., Ye, Y., Deng, Y., Bian, X., & Ding, Y.-Q. (2014) · Europe PMC (PubMed Central) · Cited by 91 · see citing works
AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation
Gao, X., Yan, F., Lin, J., Gao, L., Lu, X., Wei, S., Shen, N., Pang, J. X., Ning, Q., Komeno, Y., et al. (2015) · Leukemia · doi:10.1038/leu.2015.56 · Cited by 91 · see citing works
Mitochondrial NIX Promotes Tumor Survival in the Hypoxic Niche of Glioblastoma
Jung, J., Zhang, Y., Celiku, O., Zhang, W., Song, H., Williams, B. J., Giles, A. J., Rich, J. N., Abounader, R., Gilbert, M. R., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0198 · Cited by 91 · see citing works
“HIF-1α has been shown to regulate the self-renewal in human acute myeloid leukemia and glioblastoma (4, 6).”
BackgroundHypoxia and Hypoxia-Inducible Factors in Leukemias
Deynoux, M., Sunter, N. J., Hérault, O., & Mazurier, F. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00041 · Cited by 87 · see citing works
“Disease severity and survival have been shown to be influenced by HIF-1alpha levels, in AML and myelodysplastic syndromes (84, 88, 89); the protein expression of HIF-2alpha, usually absent in normal cells, has been observed in both AML and ALL, but has not been correlated with outcome (82, 90, 91).”
BackgroundInfluentialYan, L., Wu, M., Wang, T., Yuan, H., Zhang, X., Zhang, H., Li, T., Pandey, V., Han, X., Lobie, P. E., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-2390 · Cited by 94 · see citing works
Baumeister, J., Chatain, N., Hubrich, A., Maié, T., Costa, I. G., Denecke, B., Han, L., Küstermann, C., Sontag, S., Seré, K. M., et al. (2019) · Leukemia · doi:10.1038/s41375-019-0629-z · Cited by 86 · see citing works
“Activation of Nrf2, which is aberrantly activated in many cancers including AML, was shown to effectively reduce ROS [32].”
BackgroundInfluentialRole of hypoxia inducible factor-1 in cancer stem cells (Review)
Zhang, Q., Han, Z., Zhu, Y., Chen, J., & Li, W. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11655 · Cited by 86 · see citing works
“In addition, studies have suggested that there is negative feedback regulation of the Hes1 expres‐ sion, which is completed by the combination of Hes1 and N‐boxes on the Hes1 promoter (132).”
BackgroundInfluentialSubedi, A., Liu, Q., Ayyathan, D. M., Sharon, D. M., Cathelin, S., Hosseini, M., Xu, C., Voisin, V., Bader, G. D., D’Alessandro, A., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2021.06.004 · Cited by 88 · see citing works
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Kobayashi, M., Morinibu, A., Koyasu, S., Gotö, Y., Hiraoka, M., & Harada, H. (2017) · FEBS Journal · doi:10.1111/febs.14280 · Cited by 82 · see citing works
Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities
Marchand, T., & Pinho, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.775128 · Cited by 82 · see citing works
Control of amino acid transport coordinates metabolic reprogramming in T-cell malignancy
Grzes, K. M., Swamy, M., Hukelmann, J. L., Emslie, E., Sinclair, L. V., & Cantrell, D. A. (2017) · Leukemia · doi:10.1038/leu.2017.160 · Cited by 81 · see citing works
The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1α signaling
Jones, R. B., Dorsett, K. A., Hjelmeland, A. B., & Bellis, S. L. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001194 · Cited by 81 · see citing works
Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development
Yao, Y., Li, F., Huang, J., Jin, J., & Wang, H. (2021) · Experimental Hematology and Oncology · doi:10.1186/s40164-021-00233-2 · Cited by 86 · see citing works
“HIF-1 or HIF-2 knockdown in AML patient samples compromised their ability to reconstitute AML upon transplantation into recipient mice [53, 89].”
BackgroundMuramatsu, S., Tanaka, S., Mogushi, K., Adikrisna, R., Aihara, A., Ban, D., Ochiai, T., Irie, T., Kudo, A., Nakamura, N., et al. (2013) · Hepatology · doi:10.1002/hep.26345 · Cited by 77 · see citing works
“transplantable human AML in xenogeneic models by preferential elimination of CSCs.(25) Similar to CoCl2 treatment, hypoxic conditions also increased the proportion of Gdeg HCC cells (Fig.”
BackgroundHypoxia- and MicroRNA-Induced Metabolic Reprogramming of Tumor-Initiating Cells
Ullmann, P., Nurmik, M., Begaj, R., Haan, S., & Letellier, E. (2019) · Cells · doi:10.3390/cells8060528 · Cited by 77 · see citing works
“Along similar lines, Wang and colleagues could observe that the pharmacological inhibition of HIF1A eliminates hematological TICs [45].”
BackgroundStem cells in tissues, organoids, and cancers
Wang, X. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03199-x · Cited by 77 · see citing works
“Inhibiting hypoxia-inducible factors in hematological malignancies attenuates the tumor-propagating potential of leukemic and lymphoma CSCs [104].”
BackgroundWu, S., Kasim, V., Kano, M. R., Tanaka, S., Ohba, S., Miura, Y., Miyata, K., Liu, X., Matsuhashi, A., Chung, U., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-0366 · Cited by 77 · see citing works
Motevaseli, E., Dianatpour, A., & Ghafouri‐Fard, S. (2017) · PubMed Central · doi:10.22088/acadpub.bums.6.2.1 · Cited by 77 · see citing works
“72 Int J Mol Cell Med Spring 2017; Vol 6 No 2 HIF-1α signaling in the stem cells of mouse lymphoma and human acute myeloid leukemia and the effect of their inhibitors in preferential eradication of CSCs in mouse models (38), modulation of HIF-1α signaling following treatment with lactobacilli might be of therapeutic v…”
BackgroundShan, Q., Yin, L., Zhan, Q., et al. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01963-5 · Cited by 76 · see citing works
Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance
Vukovic, M., Guitart, A. V., Sepúlveda, C., Villacreces, A., O’Duibhir, E., Panagopoulou, T. I., Ivens, A. C., Menendez-Gonzalez, J. B., Iglesias, J. M., Allen, L., et al. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20150452 · Cited by 76 · see citing works
“Gene knockdown studies suggested the requirement for HIF-1α or HIF-2α in human LSC functions, indicating that HIFs are potential therapeutic targets for AML LSC elimination (Wang et al., 2011; Rouault-Pierre et al., 2013).”
BackgroundInfluentialRouger, J., Jakobczyk, H., Debaize, L. L., Cousin, É., Galibert, M., Troadec, M., & Gandemer, V. (2019) · Blood Reviews · doi:10.1016/j.blre.2019.04.003 · Cited by 76 · see citing works
“preclinical or early clinical studies have been published [246,247].”
BackgroundHypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models
Benito, J., Ramirez, M. S., Zacharias, N. M., Vélez, J., Harutyunyan, K. G., Lu, H., Shi, Y.-X., Matre, P. R., Jacamo, R. O., Ma, H., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3378 · Cited by 75 · see citing works
“Very recently, both HIF-1 and HIF-2 have been implicated in the maintenance of leukemia-initiating cells (50, 51), but these transcription factors remain challenging drug targets, with no selective inhibitors available in clinical practice.”
Cao, L., Fan, X., Jing, W., Liang, Y., Chen, R., Liu, Y., Zhu, M., Jia, R., Wang, H., Zhang, X., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3113 · Cited by 74 · see citing works
“The HIF1α-Notch pathway is proposed to be essential for maintenance of CSCs in hematological malignancies under conditions of normoxia [44].”
BackgroundMitochondrial metabolism as a target for acute myeloid leukemia treatment
Panina, S., Pei, J., & Kirienko, N. V. (2021) · Cancer & Metabolism · doi:10.1186/s40170-021-00253-w · Cited by 74 · see citing works
“LSCs respond to this threat by upregulating autophagy (which is critical for the maintenance of stemness and the elimination of damaged mitochondria that will produce excess ROS) and upregulate the expression of the hypoxic response transcription factor HIF-1α, even in normoxia, to further limit ROS production [25, 26…”
BackgroundRhee, H., Nahm, J. H., Kim, H., Choi, G. H., Yoo, J. E., Lee, H. S., Koh, M. J., & Park, Y. N. (2016) · Modern Pathology · doi:10.1038/modpathol.2016.111 · Cited by 74 · see citing works
Hypoxia regulates the hematopoietic stem cell niche
Morikawa, T., & Takubo, K. (2015) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-015-1743-z · Cited by 72 · see citing works
“For example, AML stem cells stabilize HIF-1α under normoxia and activate hypoxia response pathways [74].”
BackgroundHematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities
O’Reilly, E., Zeinabad, H. A., & Szegezdi, É. (2021) · Blood Reviews · doi:10.1016/j.blre.2021.100850 · Cited by 72 · see citing works
Cancer stem cells: a potential target for cancer therapy
Qiu, H. Y., Fang, X., Luo, Q., & Ouyang, G. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1920-4 · Cited by 71 · see citing works
Hypoxia-Induced Phenotypes that Mediate Tumor Heterogeneity
Qian, J., & Rankin, E. B. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12734-3_3 · Cited by 71 · see citing works
Annexin A3 as a Potential Target for Immunotherapy of Liver Cancer Stem-Like Cells
Pan, Q., Pan, K., Wang, Q.-J., Weng, D., Zhao, J.-J., Zheng, H.-X., Zhang, X.-F., Jiang, S.-S., Lv, L., Tang, Y., et al. (2014) · Stem Cells · doi:10.1002/stem.1850 · Cited by 71 · see citing works
Hypoxia, stem cells and bone tumor
Zeng, W., Wan, R., Zheng, Y., Singh, S. R., & Wei, Y. (2011) · Cancer Letters · doi:10.1016/j.canlet.2011.09.023 · Cited by 71 · see citing works
“Further, recent studies suggest that HIF is highly expressed in CSC in several tumors and blocking HIF-1α or HIF-2α activity results in dramatic decrease in CSC proliferation and self-renewal [88-91].”
Background(2019) · Advances in Cancer Research · doi:10.1016/bs.acr.2018.11.001 · Cited by 71 · see citing works
Wang, Y., Liu, Y., Tang, F., Bernot, K. M., Schore, R., Marcucci, G., Caligiuri, M. A., Zheng, P., & Liu, Y. (2014) · Blood · doi:10.1182/blood-2013-12-544221 · Cited by 69 · see citing works
“Our previous study showed that stem cell activity in mouse acute T-lymphoblastic leukemia and human AML depends on constitutive HIF activity under normoxia and is highly sensitive to echinomycin.(18) To determine whether relapsed Mll:Flt3 AML also contains a subset of cells with HIF activity under normoxia, we used th…”
BackgroundMethodInfluentialHypoxia-induced cell stemness leads to drug resistance and poor prognosis in lung adenocarcinoma
Zhao, M., Zhang, Y., Zhang, H., Wang, S., Zhang, M., Chen, X., Wang, H., Zeng, G., Chen, X., Liu, G., et al. (2014) · Lung Cancer · doi:10.1016/j.lungcan.2014.11.017 · Cited by 69 · see citing works
Liu, Y., Chen, F., Wang, S., Guo, X., Shi, P., Wang, W., & Xu, B. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.467 · Cited by 70 · see citing works
- Authors
- Wang, Y., Liu, Y., Malek, S. N., Zheng, P., & Liu, Y.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Zheng, Pan
- Liu, Yang
- Venue
- Cell stem cell
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 8
- Issue
- 4
- Pages
- 399-411
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC3084595
- OpenAlex
- W2165805414
- Semantic Scholar
- ffff27b71822b9f370ac769d66093054de794208
- Cited by
- 410
- References
- 53
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 16 · 2023: 19 · 2022: 29 · 2021: 38 · 2020: 21 · 2019: 32 · 2018: 30 · 2017: 22 · 2016: 34 · 2015: 34 · 2014: 40 · 2013: 33 · 2012: 28
- FWCI
- 12.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 838 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ai064350-15)
- National Institute on Aging (R01AG036690)
- National Cancer Institute (R01CA058033)
- National Institute of General Medical Sciences (RC1GM091648)
- National Institute of Allergy and Infectious Diseases (R01-AI064350)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- HIF-1α, cancer stem cells, hematologic malignancies, acute myeloid leukemia, mouse lymphoma, Notch signaling, echinomycin, HIF inhibitors, hypoxia, normoxic conditions, colony-forming units, xenograft models
- MeSH terms
- Animals, Humans, Lymphoma, Neoplasms, Experimental, Protein Binding, Transplantation, Heterologous, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Hematologic Neoplasms, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Receptors, Notch
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