TThe role of hypoxia-inducible factors in leukemias

Abstract

Hypoxia, understood as low partial oxygen pressure, has become one of the most explored fields in recent years. Cellular response to hypoxia is mediated by hypoxia-inducible factors (HIFs) -potent transcription regulators, and their downstream pathways. In general, HIFs modify energy metabolism, inflammation and immune response, enhance cancer invasion, metastasis, resistance to treatment, and relapse. The influence of HIFs on the progression of leukemia is still under investigation in various studies, but in mice and some human models HIFs have been recognized as leukemia immortalizers by promoting leukemic stem cell quiescence and inhibiting their cell cycle. This makes leukemic stem cells resistant to most known treatment approaches. The role of HIFs in solid tumors and leukemia makes them almost ideal targets for an anticancer treatment. Although the first attempts with new molecules are encouraging, there is a need to investigate the ambiguous role of HIFs to develop a modern antileukemic treatment.

Pharmacological or genetic inhibition of hypoxia signaling attenuates oncogenic RAS-induced cancer phenotypes

“…Activated HIFs lead to changes in the microenvironment that support tumor survival and growth, such as angiogenesis (Bousquet et al, 2016;Talks et al, 2000). In addition to the role of HIFs in solid tumors, HIF-mediated signaling has been found to play a crucial role in leukemia (Deynoux et al, 2016;Szymczak et al, 2018;Wang et al, 2011b). And activated KRAS has been shown to induce HIF1A and ARNT target genes expression in human colon cancer cells (Chun et al, 2010).…”

“…This model exhibits a dramatic increase of hemocyte numbers caused by over-proliferation, which provides an ideal phenotype for genetic and drug screens. Using this model in a genetic screen, we identified 24 promising hits that when silenced in the hemocytes, attenuated the Disease Models & Mechanisms • DMM • Accepted manuscript leukemia phenotype of the KRAS G12V model, including two key components of the hypoxia pathway, HIF1A and ARNT (HIF1B), which are involved in the development of both solid tumors and hematological malignancies (Deynoux et al, 2016;Jun et al, 2017;Semenza, 2003;Szymczak et al, 2018) . A drug screen using the same model revealed echinomycin, an inhibitor of HIF1A, could antagonize the KRAS G12V induced leukemia phenotype.…”

Hypoxia-Inducible Factors and Burn-Associated Acute Kidney Injury—A New Paradigm?

“…Additionally, patients diagnosed with type 2 diabetes have renal hypoxia, OS, endoplasmic stress, and a nutritional deficiency that will cause HIF-1α activation and HIF-2α suppression. Studies performed so far reported that high expression levels of HIFs are correlated with poor prognosis for various cancer types [ 4 , 51 , 52 , 53 , 54 ]. Pancreatic beta cells can be subjected to O 2 deprivation, so hypoxia can contribute to beta cells damage [ 55 ].…”

“…On the other hand, O 2 deprivation induces stress in living cells, linked with free-radical accumulation and oxidative stress (OS) development [ 3 ]. Hypoxia is established when the overall oxygen pressure is less than 40 mmHg in cells or tissues [ 4 ]. However, tissues and cells have different degrees of hypoxia [ 5 ].…”