title: 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 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.
authors.affiliation: Department of Pediatrics.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Silveira
authors.forename: Bruno M R
authors.initials: BM
authors.lastname: Freire
authors.forename: Kleiton S
authors.initials: KS
authors.lastname: Borges
authors.forename: Augusto F
authors.initials: AF
authors.lastname: Andrade
authors.forename: Gustavo A V
authors.initials: GA
authors.lastname: Cruzeiro
authors.forename: João Paulo J
authors.initials: JP
authors.lastname: Sabino
authors.forename: Mogens Lesner
authors.initials: ML
authors.lastname: Glass
authors.forename: José Andres
authors.initials: JA
authors.lastname: Yunes
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Brandalise
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: Tone
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Scrideli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D007223:Infant; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger
keywords: ALL; Hypoxia; gene expression profile; treatment outcome