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Hypoxia-related gene expression profile in childhood acute lymphoblastic leukemia: prognostic implications
Abstract A cellular hypoxic condition is a key event in several human cancers, but knowledge about its role in childhood acute lymphoblastic leukemia (ALL) is very limited. In the present study, the gene expression profile of hypoxia-related genes (HIF1A, CA9, VEGF and SCL2A1) was evaluated in bone...
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| Published in: | Leukemia & lymphoma 2014-08, Vol.55 (8), p.1751-1757 |
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| creator | Silveira, Vanessa S. Freire, Bruno M. R. Borges, Kleiton S. Andrade, Augusto F. Cruzeiro, Gustavo A. V. Sabino, João Paulo J. Glass, Mogens Lesner Yunes, José Andres Brandalise, Silvia Regina Tone, Luiz Gonzaga Scrideli, Carlos Alberto |
| description | Abstract
A cellular hypoxic condition is a key event in several human cancers, but knowledge about its role in childhood acute lymphoblastic leukemia (ALL) is very limited. In the present study, the gene expression profile of hypoxia-related genes (HIF1A, CA9, VEGF and SCL2A1) was evaluated in bone marrow samples of 113 pediatric patients. HIF1A mRNA up-regulation was significantly associated with higher 5-year event-free survival rates in patients with B-ALL as well as in the overall ALL population in both univariate and multivariate analysis (p = 0.023 and p = 0.041, respectively). In gene expression analysis, low oxygen levels promoted HIF1A activation in a time-dependent manner, in both ALL cell lines. In vitro cytotoxic assays suggested an initial trend toward hypoxia-related resistance in the first 24 h, but evaluation at later time points (48-72 h) clearly showed that there was no relevant difference in drug response when comparing hypoxic and normal oxygen level conditions. Modulation of mRNA expression of several hypoxia-related genes was also observed after hypoxic exposure in a cell specific manner, suggesting that HIF1A mRNA expression could play a different role in specific subtypes of leukemia. Despite the remaining questions regarding hypoxia-mediated mechanisms, these findings could be helpful to provide new insights into the role of hypoxia in childhood ALL. |
| doi_str_mv | 10.3109/10428194.2013.858812 |
| format | article |
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A cellular hypoxic condition is a key event in several human cancers, but knowledge about its role in childhood acute lymphoblastic leukemia (ALL) is very limited. In the present study, the gene expression profile of hypoxia-related genes (HIF1A, CA9, VEGF and SCL2A1) was evaluated in bone marrow samples of 113 pediatric patients. HIF1A mRNA up-regulation was significantly associated with higher 5-year event-free survival rates in patients with B-ALL as well as in the overall ALL population in both univariate and multivariate analysis (p = 0.023 and p = 0.041, respectively). In gene expression analysis, low oxygen levels promoted HIF1A activation in a time-dependent manner, in both ALL cell lines. In vitro cytotoxic assays suggested an initial trend toward hypoxia-related resistance in the first 24 h, but evaluation at later time points (48-72 h) clearly showed that there was no relevant difference in drug response when comparing hypoxic and normal oxygen level conditions. Modulation of mRNA expression of several hypoxia-related genes was also observed after hypoxic exposure in a cell specific manner, suggesting that HIF1A mRNA expression could play a different role in specific subtypes of leukemia. Despite the remaining questions regarding hypoxia-mediated mechanisms, these findings could be helpful to provide new insights into the role of hypoxia in childhood ALL.</description><identifier>ISSN: 1042-8194</identifier><identifier>EISSN: 1029-2403</identifier><identifier>DOI: 10.3109/10428194.2013.858812</identifier><identifier>PMID: 24160851</identifier><language>eng</language><publisher>United States: Informa Healthcare</publisher><subject>ALL ; Antineoplastic Agents - pharmacology ; Cell Hypoxia ; Cell Line, Tumor ; Cell Proliferation ; Child ; Child, Preschool ; gene expression profile ; Gene Expression Regulation, Leukemic - drug effects ; Humans ; Hypoxia ; Hypoxia - genetics ; Infant ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality ; Prognosis ; RNA, Messenger - genetics ; Transcriptional Activation ; Transcriptome ; treatment outcome</subject><ispartof>Leukemia & lymphoma, 2014-08, Vol.55 (8), p.1751-1757</ispartof><rights>2014 Informa UK, Ltd. 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-2827e58eba22deaef329ab818594261d3a8930432fb2f9d97f69e57b9f5308603</citedby><cites>FETCH-LOGICAL-c418t-2827e58eba22deaef329ab818594261d3a8930432fb2f9d97f69e57b9f5308603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24160851$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Silveira, Vanessa S.</creatorcontrib><creatorcontrib>Freire, Bruno M. R.</creatorcontrib><creatorcontrib>Borges, Kleiton S.</creatorcontrib><creatorcontrib>Andrade, Augusto F.</creatorcontrib><creatorcontrib>Cruzeiro, Gustavo A. V.</creatorcontrib><creatorcontrib>Sabino, João Paulo J.</creatorcontrib><creatorcontrib>Glass, Mogens Lesner</creatorcontrib><creatorcontrib>Yunes, José Andres</creatorcontrib><creatorcontrib>Brandalise, Silvia Regina</creatorcontrib><creatorcontrib>Tone, Luiz Gonzaga</creatorcontrib><creatorcontrib>Scrideli, Carlos Alberto</creatorcontrib><title>Hypoxia-related gene expression profile in childhood acute lymphoblastic leukemia: prognostic implications</title><title>Leukemia & lymphoma</title><addtitle>Leuk Lymphoma</addtitle><description>Abstract
A cellular hypoxic condition is a key event in several human cancers, but knowledge about its role in childhood acute lymphoblastic leukemia (ALL) is very limited. In the present study, the gene expression profile of hypoxia-related genes (HIF1A, CA9, VEGF and SCL2A1) was evaluated in bone marrow samples of 113 pediatric patients. HIF1A mRNA up-regulation was significantly associated with higher 5-year event-free survival rates in patients with B-ALL as well as in the overall ALL population in both univariate and multivariate analysis (p = 0.023 and p = 0.041, respectively). In gene expression analysis, low oxygen levels promoted HIF1A activation in a time-dependent manner, in both ALL cell lines. In vitro cytotoxic assays suggested an initial trend toward hypoxia-related resistance in the first 24 h, but evaluation at later time points (48-72 h) clearly showed that there was no relevant difference in drug response when comparing hypoxic and normal oxygen level conditions. Modulation of mRNA expression of several hypoxia-related genes was also observed after hypoxic exposure in a cell specific manner, suggesting that HIF1A mRNA expression could play a different role in specific subtypes of leukemia. Despite the remaining questions regarding hypoxia-mediated mechanisms, these findings could be helpful to provide new insights into the role of hypoxia in childhood ALL.</description><subject>ALL</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Hypoxia</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>gene expression profile</subject><subject>Gene Expression Regulation, Leukemic - drug effects</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Hypoxia - genetics</subject><subject>Infant</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality</subject><subject>Prognosis</subject><subject>RNA, Messenger - genetics</subject><subject>Transcriptional Activation</subject><subject>Transcriptome</subject><subject>treatment outcome</subject><issn>1042-8194</issn><issn>1029-2403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNp9kE1v1DAQhi1UREvLP0BVjr1k8VeyNgdQVRWKVIkLPVsTZ9x468TBTtTuvydhWyQuPXlkPe87o4eQj4xuBKP6E6OSK6blhlMmNqpSivE35IRRrksuqThaZ8nLlTkm73PeUUorXfN35JhLVlNVsROyu9mP8clDmTDAhG1xjwMW-DQmzNnHoRhTdD5g4YfCdj60XYxtAXaesAj7fuxiEyBP3hYB5wfsPXxeI_dD_Pvp-zF4C9PSlM_IWwch44fn95Tcfbv-dXVT3v78_uPq8ra0kqmp5IpvsVLYAOctAjrBNTSKqUpLXrNWgNKCSsFdw51u9dbVGqtto10lqKqpOCUXh97ljt8z5sn0PlsMAQaMczaskosTUYvtgsoDalPMOaEzY_I9pL1h1KyWzYtls1o2B8tL7Px5w9z02P4LvWhdgK8HwA8uph4eYwqtmWAfYnIJBuvzWv_qii__NXQIYeosJDS7OKdhEfj6jX8A6sKg6A</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Silveira, Vanessa S.</creator><creator>Freire, Bruno M. R.</creator><creator>Borges, Kleiton S.</creator><creator>Andrade, Augusto F.</creator><creator>Cruzeiro, Gustavo A. V.</creator><creator>Sabino, João Paulo J.</creator><creator>Glass, Mogens Lesner</creator><creator>Yunes, José Andres</creator><creator>Brandalise, Silvia Regina</creator><creator>Tone, Luiz Gonzaga</creator><creator>Scrideli, Carlos Alberto</creator><general>Informa Healthcare</general><general>Taylor & Francis</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20140801</creationdate><title>Hypoxia-related gene expression profile in childhood acute lymphoblastic leukemia: prognostic implications</title><author>Silveira, Vanessa S. ; Freire, Bruno M. R. ; Borges, Kleiton S. ; Andrade, Augusto F. ; Cruzeiro, Gustavo A. V. ; Sabino, João Paulo J. ; Glass, Mogens Lesner ; Yunes, José Andres ; Brandalise, Silvia Regina ; Tone, Luiz Gonzaga ; Scrideli, Carlos Alberto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-2827e58eba22deaef329ab818594261d3a8930432fb2f9d97f69e57b9f5308603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>ALL</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Hypoxia</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>gene expression profile</topic><topic>Gene Expression Regulation, Leukemic - drug effects</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Hypoxia - genetics</topic><topic>Infant</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality</topic><topic>Prognosis</topic><topic>RNA, Messenger - genetics</topic><topic>Transcriptional Activation</topic><topic>Transcriptome</topic><topic>treatment outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Silveira, Vanessa S.</creatorcontrib><creatorcontrib>Freire, Bruno M. R.</creatorcontrib><creatorcontrib>Borges, Kleiton S.</creatorcontrib><creatorcontrib>Andrade, Augusto F.</creatorcontrib><creatorcontrib>Cruzeiro, Gustavo A. V.</creatorcontrib><creatorcontrib>Sabino, João Paulo J.</creatorcontrib><creatorcontrib>Glass, Mogens Lesner</creatorcontrib><creatorcontrib>Yunes, José Andres</creatorcontrib><creatorcontrib>Brandalise, Silvia Regina</creatorcontrib><creatorcontrib>Tone, Luiz Gonzaga</creatorcontrib><creatorcontrib>Scrideli, Carlos Alberto</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Leukemia & lymphoma</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Silveira, Vanessa S.</au><au>Freire, Bruno M. R.</au><au>Borges, Kleiton S.</au><au>Andrade, Augusto F.</au><au>Cruzeiro, Gustavo A. V.</au><au>Sabino, João Paulo J.</au><au>Glass, Mogens Lesner</au><au>Yunes, José Andres</au><au>Brandalise, Silvia Regina</au><au>Tone, Luiz Gonzaga</au><au>Scrideli, Carlos Alberto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypoxia-related gene expression profile in childhood acute lymphoblastic leukemia: prognostic implications</atitle><jtitle>Leukemia & lymphoma</jtitle><addtitle>Leuk Lymphoma</addtitle><date>2014-08-01</date><risdate>2014</risdate><volume>55</volume><issue>8</issue><spage>1751</spage><epage>1757</epage><pages>1751-1757</pages><issn>1042-8194</issn><eissn>1029-2403</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Abstract
A cellular hypoxic condition is a key event in several human cancers, but knowledge about its role in childhood acute lymphoblastic leukemia (ALL) is very limited. In the present study, the gene expression profile of hypoxia-related genes (HIF1A, CA9, VEGF and SCL2A1) was evaluated in bone marrow samples of 113 pediatric patients. HIF1A mRNA up-regulation was significantly associated with higher 5-year event-free survival rates in patients with B-ALL as well as in the overall ALL population in both univariate and multivariate analysis (p = 0.023 and p = 0.041, respectively). In gene expression analysis, low oxygen levels promoted HIF1A activation in a time-dependent manner, in both ALL cell lines. In vitro cytotoxic assays suggested an initial trend toward hypoxia-related resistance in the first 24 h, but evaluation at later time points (48-72 h) clearly showed that there was no relevant difference in drug response when comparing hypoxic and normal oxygen level conditions. Modulation of mRNA expression of several hypoxia-related genes was also observed after hypoxic exposure in a cell specific manner, suggesting that HIF1A mRNA expression could play a different role in specific subtypes of leukemia. Despite the remaining questions regarding hypoxia-mediated mechanisms, these findings could be helpful to provide new insights into the role of hypoxia in childhood ALL.</abstract><cop>United States</cop><pub>Informa Healthcare</pub><pmid>24160851</pmid><doi>10.3109/10428194.2013.858812</doi><tpages>7</tpages></addata></record> |
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| subjects | ALL Antineoplastic Agents - pharmacology Cell Hypoxia Cell Line, Tumor Cell Proliferation Child Child, Preschool gene expression profile Gene Expression Regulation, Leukemic - drug effects Humans Hypoxia Hypoxia - genetics Infant Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality Prognosis RNA, Messenger - genetics Transcriptional Activation Transcriptome treatment outcome |
| title | Hypoxia-related gene expression profile in childhood acute lymphoblastic leukemia: prognostic implications |
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