{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T07:24:26Z","timestamp":1770276266549,"version":"3.49.0"},"reference-count":55,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Special Account for Research Grants of National and Kapodistrian University of Athens","award":["."],"award-info":[{"award-number":["."]}]},{"name":"Hellenic Society of Hematology","award":["."],"award-info":[{"award-number":["."]}]},{"name":"European Commission grant","award":["H2020-668353"],"award-info":[{"award-number":["H2020-668353"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem (HSCs) and\/or progenitor cells disorders. The established dependence of MDS progenitors on the hypoxic bone marrow (BM) microenvironment turned scientific interests to the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 facilitates quiescence maintenance and regulates differentiation by manipulating HSCs metabolism, being thus an appealing research target. Therefore, we examine the aberrant HIF-1 stabilization in BMs from MDS patients and controls (CTRLs). Using a nitroimidazole\u2013indocyanine conjugate, we show that HIF-1 aberrant expression and transcription activity is oxygen independent, establishing the phenomenon of pseudohypoxia in MDS BM. Next, we examine mitochondrial quality and quantity along with levels of autophagy in the differentiating myeloid lineage isolated from fresh BM MDS and CTRL aspirates given that both phenomena are HIF-1 dependent. We show that the mitophagy of abnormal mitochondria and autophagic death are prominently featured in the MDS myeloid lineage, their severity increasing with intra-BM blast counts. Finally, we use in vitro cultured CD34+ HSCs isolated from fresh human BM aspirates to manipulate HIF-1 expression and examine its potential as a therapeutic target. We find that despite being cultured under 21% FiO2, HIF-1 remained aberrantly stable in all MDS cultures. Inhibition of the HIF-1\u03b1 subunit had a variable beneficial effect in all &lt;5%-intra-BM blasts-MDS, while it had no effect in CTRLs or in \u22655%-intra-BM blasts-MDS that uniformly died within 3 days of culture. We conclude that HIF-1 and pseudohypoxia are prominently featured in MDS pathobiology, and their manipulation has some potential in the therapeutics of benign MDS.<\/jats:p>","DOI":"10.3390\/ijms22084099","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T12:11:00Z","timestamp":1618488660000},"page":"4099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Exploiting the Role of Hypoxia-Inducible Factor 1 and Pseudohypoxia in the Myelodysplastic Syndrome Pathophysiology"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9977-4035","authenticated-orcid":false,"given":"Ioanna E.","family":"Stergiou","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantinos","family":"Kambas","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-4163","authenticated-orcid":false,"given":"Aikaterini","family":"Poulaki","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"},{"name":"Hematology Unit, Second Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stavroula","family":"Giannouli","sequence":"additional","affiliation":[{"name":"Hematology Unit, Second Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6263-4231","authenticated-orcid":false,"given":"Theodora","family":"Katsila","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aglaia","family":"Dimitrakopoulou","sequence":"additional","affiliation":[{"name":"Laboratory of Flow Cytometry, Immunology Department, Laiko Hospital of Athens, 11526 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9020-8726","authenticated-orcid":false,"given":"Veroniki","family":"Vidali","sequence":"additional","affiliation":[{"name":"Laboratory of Synthesis of Natural Products and Bioorganic Chemistry, Institute of Nanoscience and Nanotechnology, National Center for Scientific Research \u201cDemokritos\u201d, 15341 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3745-7971","authenticated-orcid":false,"given":"Vasileios","family":"Mouchtouris","sequence":"additional","affiliation":[{"name":"Laboratory of Synthesis of Natural Products and Bioorganic Chemistry, Institute of Nanoscience and Nanotechnology, National Center for Scientific Research \u201cDemokritos\u201d, 15341 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ismini","family":"Kloukina","sequence":"additional","affiliation":[{"name":"Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelia","family":"Xingi","sequence":"additional","affiliation":[{"name":"Light Microscopy Unit, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stamatis N.","family":"Pagakis","sequence":"additional","affiliation":[{"name":"Biological Imaging Unit, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5931-2880","authenticated-orcid":false,"given":"Lesley","family":"Probert","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0519-7776","authenticated-orcid":false,"given":"George P.","family":"Patrinos","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Patras, 26504 Patras, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantinos","family":"Ritis","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, University General Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athanasios G.","family":"Tzioufas","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Voulgarelis","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.med.56.082103.104704","article-title":"Myelodysplastic syndrome","volume":"56","author":"Hofmann","year":"2005","journal-title":"Annu. Rev. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1182\/blood.2018884338","article-title":"Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic syndromes","volume":"134","author":"Hsu","year":"2019","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1182\/blood-2015-11-679167","article-title":"Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure","volume":"128","author":"Mossner","year":"2016","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3616","DOI":"10.1182\/blood-2013-08-518886","article-title":"Clinical and biological implications of driver mutations in myelodysplastic syndromes","volume":"122","author":"Papaemmanuil","year":"2013","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1182\/blood-2015-03-631747","article-title":"Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes","volume":"126","author":"Steensma","year":"2015","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ajhg.2017.05.013","article-title":"Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life","volume":"101","author":"Sengul","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10561","DOI":"10.18632\/oncotarget.24302","article-title":"Severe hypoxia selects hematopoietic progenitors with stem cell potential from primary Myelodysplastic syndrome bone marrow cell cultures","volume":"9","author":"Masala","year":"2018","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.exphem.2006.08.017","article-title":"Enhanced growth of myelodysplastic colonies in hypoxic conditions","volume":"35","author":"Thompson","year":"2007","journal-title":"Exp. Hematol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s12185-018-2534-z","article-title":"Metabolism as master of hematopoietic stem cell fate","volume":"109","author":"Ito","year":"2019","journal-title":"Int. J. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.tcb.2014.04.001","article-title":"Surviving change: The metabolic journey of hematopoietic stem cells","volume":"24","author":"Kohli","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.stem.2011.09.010","article-title":"Metabolic regulation of hematopoietic stem cells in the hypoxic niche","volume":"9","author":"Suda","year":"2011","journal-title":"Cell Stem. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1089\/ars.2012.5019","article-title":"Hypoxia and metabolic properties of hematopoietic stem cells","volume":"20","author":"Zhang","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.stem.2010.06.020","article-title":"Regulation of the HIF-1alpha level is essential for hematopoietic stem cells","volume":"7","author":"Takubo","year":"2010","journal-title":"Cell Stem. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5510","DOI":"10.1073\/pnas.92.12.5510","article-title":"Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension","volume":"92","author":"Wang","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.cmet.2006.02.002","article-title":"HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia","volume":"3","author":"Kim","year":"2006","journal-title":"Cell Metab."},{"key":"ref_17","first-page":"165","article-title":"Targeted genes and interacting proteins of hypoxia inducible factor-1","volume":"3","author":"Liu","year":"2012","journal-title":"Int. J. Biochem. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23111","DOI":"10.1074\/jbc.M202487200","article-title":"Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis","volume":"277","author":"Lu","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20070389","article-title":"Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1","volume":"405","author":"Semenza","year":"2007","journal-title":"Biochem. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10892","DOI":"10.1074\/jbc.M800102200","article-title":"Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia","volume":"283","author":"Zhang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41590-017-0008-8","article-title":"Hyperactivated mitophagy in hematopoietic stem cells","volume":"19","author":"Yang","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1128\/MCB.22.7.2283-2293.2002","article-title":"Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis","volume":"22","author":"Shoshani","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1111\/cas.13990","article-title":"Hypoxia\/pseudohypoxia-mediated activation of hypoxia-inducible factor-1\u03b1 in cancer","volume":"110","author":"Hayashi","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"286","DOI":"10.3389\/fonc.2017.00286","article-title":"Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer","volume":"7","author":"Iommarini","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_26","first-page":"29","article-title":"The Use of Correlative Light-Electron Microscopy (CLEM) to Study PINK1\/Parkin-Mediated Mitophagy","volume":"1759","author":"Buss","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gustafson, M.P., Lin, Y., Maas, M.L., Van Keulen, V.P., Johnston, P.B., Peikert, T., Gastineau, D.A., and Dietz, A.B. (2015). A method for identification and analysis of non-overlapping myeloid immunophenotypes in humans. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121546"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/BF01081524","article-title":"Nitroimidazoles and imaging hypoxia","volume":"22","author":"Nunn","year":"1995","journal-title":"Eur. J. Nucl. Med."},{"key":"ref_29","first-page":"155","article-title":"Glutathione depletion by 2-nitroimidazole-1-acetohydroxamic acid as a radiosensitizer in hypoxic rat hepatocytes","volume":"17","author":"Takanuki","year":"1988","journal-title":"Biochem. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"687","DOI":"10.2174\/187152011796817664","article-title":"Nitroimidazoles as anti-tumor agents","volume":"11","author":"Liu","year":"2011","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"129s","DOI":"10.2967\/jnumed.107.045914","article-title":"Molecular imaging of hypoxia","volume":"49","author":"Krohn","year":"2008","journal-title":"J. Nucl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Westrate, L.M., Drocco, J.A., Martin, K.R., Hlavacek, W.S., and MacKeigan, J.P. (2014). Mitochondrial morphological features are associated with fission and fusion events. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095265"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.3324\/haematol.13563","article-title":"Apoptotic pathways to death in myelodysplastic syndromes","volume":"93","author":"Michaela","year":"2008","journal-title":"Haematologica"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Poulaki, A., Katsila, T., Stergiou, I.E., Giannouli, S., G\u03ccmez-Tamayo, J.C., Piperaki, E.T., Kambas, K., Dimitrakopoulou, A., Patrinos, G.P., and Tzioufas, A.G. (2020). Bioenergetic Profiling of the Differentiating Human MDS Myeloid Lineage with Low and High Bone Marrow Blast Counts. Cancers, 12.","DOI":"10.3390\/cancers12123520"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.bbabio.2008.05.001","article-title":"Mitochondrial fusion, fission and autophagy as a quality control axis: The bioenergetic view","volume":"1777","author":"Twig","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/sj.emboj.7601963","article-title":"Fission and selective fusion govern mitochondrial segregation and elimination by autophagy","volume":"27","author":"Twig","year":"2008","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.cmet.2013.03.002","article-title":"Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure","volume":"17","author":"Liesa","year":"2013","journal-title":"Cell Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1101\/gad.1256804","article-title":"Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1\/TSC2 tumor suppressor complex","volume":"18","author":"Brugarolas","year":"2004","journal-title":"Genes Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1128\/MCB.00166-09","article-title":"Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains","volume":"29","author":"Bellot","year":"2009","journal-title":"Mol. Cell Biol"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1111\/febs.13962","article-title":"Mechanistic roles of autophagy in hematopoietic differentiation","volume":"284","author":"Riffelmacher","year":"2017","journal-title":"FEBS J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.immuni.2017.08.005","article-title":"Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation","volume":"47","author":"Riffelmacher","year":"2017","journal-title":"Immunity"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/cdd.2014.143","article-title":"Autosis and autophagic cell death: The dark side of autophagy","volume":"22","author":"Liu","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"20364","DOI":"10.1073\/pnas.1319661110","article-title":"Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia","volume":"110","author":"Liu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1158\/2159-8290.CD-17-1203","article-title":"Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes","volume":"8","author":"Hayashi","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"245","DOI":"10.2174\/1568009611313030003","article-title":"Oxygen-independent regulation of HIF-1: Novel involvement of PI3K\/AKT\/mTOR pathway in cancer","volume":"13","author":"Agani","year":"2013","journal-title":"Curr Cancer Drug Targets"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.jbior.2012.04.002","article-title":"PI3K keeps the balance between metabolism and cancer","volume":"52","author":"Braccini","year":"2012","journal-title":"Adv. Biol. Regul."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Nepstad, I., Hatfield, K.J., Gr\u00f8nnings\u00e6ter, I.S., and Reikvam, H. (2020). The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082907"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/sj.leu.2404057","article-title":"Frequent elevation of Akt kinase phosphorylation in blood marrow and peripheral blood mononuclear cells from high-risk myelodysplastic syndrome patients","volume":"20","author":"Tazzari","year":"2006","journal-title":"Leukemia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1158\/0008-5472.CAN-06-4409","article-title":"The Akt\/Mammalian Target of Rapamycin Signal Transduction Pathway Is Activated in High-Risk Myelodysplastic Syndromes and Influences Cell Survival and Proliferation","volume":"67","author":"Follo","year":"2007","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"30520","DOI":"10.1074\/jbc.M004630200","article-title":"A role for nuclear phospholipase Cbeta 1 in cell cycle control","volume":"275","author":"Faenza","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_51","first-page":"2978","article-title":"Phosphoinositide signaling in nuclei of Friend cells: Tiazofurin down-regulates phospholipase C beta 1","volume":"55","author":"Manzoli","year":"1995","journal-title":"Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1038\/leu.2012.133","article-title":"Activation of nuclear inositide signalling pathways during erythropoietin therapy in low-risk MDS patients","volume":"26","author":"Follo","year":"2012","journal-title":"Leukemia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/leu.2010.266","article-title":"Synergistic induction of PI-PLC\u03b21 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes","volume":"25","author":"Follo","year":"2011","journal-title":"Leukemia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.dyepig.2010.08.008","article-title":"Synthesis and fluorescent characteristics of imidazole\u2013indocyanine green conjugates","volume":"89","author":"Pavlik","year":"2011","journal-title":"Dyes Pigment."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Jie, Z., Zhang, Y., Wang, C., Shen, B., Guan, X., Ren, Z., Ding, X., Dai, W., and Jiang, Y. (2017). Large-scale ex vivo generation of human neutrophils from cord blood CD34+ cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180832"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4099\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:48:28Z","timestamp":1760161708000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,15]]},"references-count":55,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22084099"],"URL":"https:\/\/doi.org\/10.3390\/ijms22084099","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,15]]}}}