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.

Hypoxia and Hypoxia-Inducible Factors in Leukemias

“…Similarly, in CML, HIF-1alpha induction following short (5 h) hypoxia exposure delivered a survival signal to cells, whereas it promoted cell death within a longer period (22 h) ( 127 ). In the ALL model, 24 h-exposure to hypoxia conferred chemoresistance in contrast to longer exposure (48–72 h) ( 128 ). These data suggest that duration of hypoxia incubation may promote or inhibit leukemia progression and maintenance, thus explaining the oncogenic or tumor suppressor activity.…”

Prognostic nomogram of hypoxia-related genes predicting overall survival of colorectal cancer–Analysis of TCGA database

“…In breast cancer, analysis of HRGs has been proposed as a tool for developing novel therapeutic strategies with molecular signatures 20 . The prognostic ability of HRGs is reported in many other malignancies, including gastric cancer, leukemia, and CRC 8,21,22 .…”

History of Maternal Fetal Loss and Childhood Leukaemia Risk in Subsequent Offspring: Differentials by Miscarriage or Stillbirth History and Disease Subtype

“…In this context, recent studies have suggested that single‐nucleotide polymorphisms in genes involved in placental function may be related to both stillbirths and ALL risk. Specifically, mutations in genes critical for normal placental function, such as the endothelial nitric oxide synthase, Klotho and hypoxic inducible factor‐1α genes, as well as polymorphisms of the vascular endothelial growth factor (VEGF) and tumour necrosis factor‐α genes, may result in abnormal prenatal development, fetal growth restriction, and late fetal death . Polymorphisms of the aforementioned genes may also play a pivotal role in the induction of neovascularisation in ALL by increasing the microvascular density in the bone marrow of children .…”