Adaptive phenotypic modulations lead to therapy resistance in chronic myeloid leukemia cells
Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34(-)/CD38(-), BCR-Abl-independent, proliferate slowly, highly adherent and form...
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| Veröffentlicht in: | PloS one 2020-02, Vol.15 (2), p.e0229104-e0229104, Article 0229104 |
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| creator | Baykal-Kose, Seda Acikgoz, Eda Yavuz, Ahmet Sinan Geyik, Oyku Gonul Ate, Halil Sezerman, Osman Ugur Ozsan, Guner Hayri Yuce, Zeynep |
| description | Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34(-)/CD38(-), BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and beta-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/ organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome. |
| doi_str_mv | 10.1371/journal.pone.0229104 |
| format | Article |
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We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34(-)/CD38(-), BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and beta-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/ organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0229104</identifier><identifier>PMID: 32106243</identifier><language>eng</language><publisher>SAN FRANCISCO: Public Library Science</publisher><subject>3T3 Cells ; Abl protein ; Analysis ; Animals ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Apoptosis ; BCR protein ; BCR-ABL protein ; Biology ; Biology and Life Sciences ; Bosutinib ; Cadherins - genetics ; Cadherins - metabolism ; Cancer ; CD34 antigen ; CD38 antigen ; CD44 antigen ; CD45 antigen ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; Chromosomes ; Chronic myeloid leukemia ; Drug dosages ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; E-cadherin ; Embryology ; Environmental stress ; Enzyme inhibitors ; Epithelial-Mesenchymal Transition - drug effects ; Epithelial-Mesenchymal Transition - genetics ; Fusion protein ; Fusion Proteins, bcr-abl - antagonists & inhibitors ; Fusion Proteins, bcr-abl - genetics ; Fusion Proteins, bcr-abl - metabolism ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - drug effects ; Genes ; Genotype & phenotype ; Hematology ; Histology ; Humans ; Imatinib ; Imatinib Mesylate - pharmacology ; Imatinib Mesylate - therapeutic use ; K562 Cells ; Kinases ; Leukemia ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics ; Medicine ; Medicine and Health Sciences ; Mice ; Multidisciplinary Sciences ; Mutation ; Mutation - drug effects ; Myeloid leukemia ; Oligonucleotide Array Sequence Analysis ; Penicillin G ; Phenols (Class of compounds) ; Phenotypes ; Ponatinib ; Protein Domains - genetics ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Protein-tyrosine kinase ; Proteins ; Research and Analysis Methods ; Science & Technology ; Science & Technology - Other Topics ; Senescence ; Spheroids ; Stem cell transplantation ; Stem cells ; Transcription ; Transcription (Genetics) ; Tumors ; Tyrosine ; β-Catenin</subject><ispartof>PloS one, 2020-02, Vol.15 (2), p.e0229104-e0229104, Article 0229104</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Baykal-Köse et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Baykal-Köse et al 2020 Baykal-Köse et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>22</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000535237000018</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c692t-4982b0a07d6e79a6122573e9256ae2b57c16691765324fcc3445b15d10de1cf53</citedby><cites>FETCH-LOGICAL-c692t-4982b0a07d6e79a6122573e9256ae2b57c16691765324fcc3445b15d10de1cf53</cites><orcidid>0000-0002-6772-3081 ; 0000-0002-2762-0942 ; 0000-0001-8654-5332 ; 0000-0003-4069-6105</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046262/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046262/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2115,2929,23871,27929,27930,28253,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32106243$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Dello Sbarba, Persio</contributor><creatorcontrib>Baykal-Kose, Seda</creatorcontrib><creatorcontrib>Acikgoz, Eda</creatorcontrib><creatorcontrib>Yavuz, Ahmet Sinan</creatorcontrib><creatorcontrib>Geyik, Oyku Gonul</creatorcontrib><creatorcontrib>Ate, Halil</creatorcontrib><creatorcontrib>Sezerman, Osman Ugur</creatorcontrib><creatorcontrib>Ozsan, Guner Hayri</creatorcontrib><creatorcontrib>Yuce, Zeynep</creatorcontrib><title>Adaptive phenotypic modulations lead to therapy resistance in chronic myeloid leukemia cells</title><title>PloS one</title><addtitle>PLOS ONE</addtitle><addtitle>PLoS One</addtitle><description>Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34(-)/CD38(-), BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and beta-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/ organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome.</description><subject>3T3 Cells</subject><subject>Abl protein</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Apoptosis</subject><subject>BCR protein</subject><subject>BCR-ABL protein</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Bosutinib</subject><subject>Cadherins - genetics</subject><subject>Cadherins - metabolism</subject><subject>Cancer</subject><subject>CD34 antigen</subject><subject>CD38 antigen</subject><subject>CD44 antigen</subject><subject>CD45 antigen</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - genetics</subject><subject>Chromosomes</subject><subject>Chronic myeloid leukemia</subject><subject>Drug dosages</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>E-cadherin</subject><subject>Embryology</subject><subject>Environmental stress</subject><subject>Enzyme inhibitors</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Fusion protein</subject><subject>Fusion Proteins, bcr-abl - antagonists & inhibitors</subject><subject>Fusion Proteins, bcr-abl - genetics</subject><subject>Fusion Proteins, bcr-abl - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genes</subject><subject>Genotype & phenotype</subject><subject>Hematology</subject><subject>Histology</subject><subject>Humans</subject><subject>Imatinib</subject><subject>Imatinib Mesylate - pharmacology</subject><subject>Imatinib Mesylate - therapeutic use</subject><subject>K562 Cells</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Multidisciplinary Sciences</subject><subject>Mutation</subject><subject>Mutation - drug effects</subject><subject>Myeloid leukemia</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Penicillin G</subject><subject>Phenols (Class of compounds)</subject><subject>Phenotypes</subject><subject>Ponatinib</subject><subject>Protein Domains - genetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Protein-tyrosine 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phenotypic modulations lead to therapy resistance in chronic myeloid leukemia cells</title><author>Baykal-Kose, Seda ; Acikgoz, Eda ; Yavuz, Ahmet Sinan ; Geyik, Oyku Gonul ; Ate, Halil ; Sezerman, Osman Ugur ; Ozsan, Guner Hayri ; Yuce, Zeynep</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-4982b0a07d6e79a6122573e9256ae2b57c16691765324fcc3445b15d10de1cf53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>3T3 Cells</topic><topic>Abl protein</topic><topic>Analysis</topic><topic>Animals</topic><topic>Antigens, CD - genetics</topic><topic>Antigens, CD - metabolism</topic><topic>Apoptosis</topic><topic>BCR protein</topic><topic>BCR-ABL protein</topic><topic>Biology</topic><topic>Biology and Life Sciences</topic><topic>Bosutinib</topic><topic>Cadherins - genetics</topic><topic>Cadherins - metabolism</topic><topic>Cancer</topic><topic>CD34 antigen</topic><topic>CD38 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Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Baykal-Kose, Seda</au><au>Acikgoz, Eda</au><au>Yavuz, Ahmet Sinan</au><au>Geyik, Oyku Gonul</au><au>Ate, Halil</au><au>Sezerman, Osman Ugur</au><au>Ozsan, Guner Hayri</au><au>Yuce, Zeynep</au><au>Dello Sbarba, Persio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adaptive phenotypic modulations lead to therapy resistance in chronic myeloid leukemia cells</atitle><jtitle>PloS one</jtitle><stitle>PLOS ONE</stitle><addtitle>PLoS One</addtitle><date>2020-02-27</date><risdate>2020</risdate><volume>15</volume><issue>2</issue><spage>e0229104</spage><epage>e0229104</epage><pages>e0229104-e0229104</pages><artnum>0229104</artnum><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34(-)/CD38(-), BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and beta-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/ organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome.</abstract><cop>SAN FRANCISCO</cop><pub>Public Library Science</pub><pmid>32106243</pmid><doi>10.1371/journal.pone.0229104</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0002-6772-3081</orcidid><orcidid>https://orcid.org/0000-0002-2762-0942</orcidid><orcidid>https://orcid.org/0000-0001-8654-5332</orcidid><orcidid>https://orcid.org/0000-0003-4069-6105</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2020-02, Vol.15 (2), p.e0229104-e0229104, Article 0229104 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2369426486 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; Web of Science - Science Citation Index Expanded - 2020<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 3T3 Cells Abl protein Analysis Animals Antigens, CD - genetics Antigens, CD - metabolism Apoptosis BCR protein BCR-ABL protein Biology Biology and Life Sciences Bosutinib Cadherins - genetics Cadherins - metabolism Cancer CD34 antigen CD38 antigen CD44 antigen CD45 antigen Cell Proliferation - drug effects Cell Proliferation - genetics Chromosomes Chronic myeloid leukemia Drug dosages Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics E-cadherin Embryology Environmental stress Enzyme inhibitors Epithelial-Mesenchymal Transition - drug effects Epithelial-Mesenchymal Transition - genetics Fusion protein Fusion Proteins, bcr-abl - antagonists & inhibitors Fusion Proteins, bcr-abl - genetics Fusion Proteins, bcr-abl - metabolism Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Genes Genotype & phenotype Hematology Histology Humans Imatinib Imatinib Mesylate - pharmacology Imatinib Mesylate - therapeutic use K562 Cells Kinases Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics Medicine Medicine and Health Sciences Mice Multidisciplinary Sciences Mutation Mutation - drug effects Myeloid leukemia Oligonucleotide Array Sequence Analysis Penicillin G Phenols (Class of compounds) Phenotypes Ponatinib Protein Domains - genetics Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Protein-tyrosine kinase Proteins Research and Analysis Methods Science & Technology Science & Technology - Other Topics Senescence Spheroids Stem cell transplantation Stem cells Transcription Transcription (Genetics) Tumors Tyrosine β-Catenin |
| title | Adaptive phenotypic modulations lead to therapy resistance in chronic myeloid leukemia cells |
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