Hypoxia and Hypoxia-Inducible Factors in Leukemias

Abstract

Despite huge improvements in the treatment of leukemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukemic stem cells (LSCs) within the bone marrow, which are able to self-renew, and therefore reestablish the full tumor. The marrow microenvironment contributes considerably in supporting the protection and development of leukemic cells. LSCs share specific niches with normal hematopoietic stem cells with the niche itself being composed of a variety of cell types, including mesenchymal stem/stromal cells, bone cells, immune cells, neuronal cells, and vascular cells. A hallmark of the hematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of hematopoietic stem/progenitor cells. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor (HIF) family. In solid tumors, it has been well established that hypoxia triggers intrinsic metabolic changes and microenvironmental modifications, such as the stimulation of angiogenesis, through activation of HIFs. As leukemia is not considered a “solid” tumor, the role of oxygen in the disease was presumed to be inconsequential and remained long overlooked. This view has now been revised since hypoxia has been shown to influence leukemic cell proliferation, differentiation, and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumor suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukemic development and therapeutic resistance and to discuss the recent hypoxia-based strategies proposed to eradicate leukemias.

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…It is now known that bone marrow also presents hypoxic areas that can enhance leukemia progression [28]. However, this article will only focus on studies that mimic hypoxia in solid tumors.…”

The role of hypoxia-inducible factors in leukemias

“…LSCs derive from HSCs homing to the most hypoxic bone marrow areas. [43][44][45] As mentioned above, tissue oxygen concentration is much lower than in arterial blood enriched in O 2 from the lungs. In bone marrow, the oxygen concentration is even lower than in other tissues, ranging from < 6% oxygen near blood vessels to anoxia in not vascularized regions.…”

“…The components of the hematopoietic niche vary in oxygen level. 45,46 The boosting role of hypoxia in rapid growth, proliferation, metabolism, metastases and mortality of solid tumors has been described. 47 The role of hypoxia in leukemias is not as well established, but the hypoxic BM niche increases poor response to treatment.…”

“…47 The role of hypoxia in leukemias is not as well established, but the hypoxic BM niche increases poor response to treatment. 45 It is accepted that gradients of O 2 from below 1% in the hypoxic niche to 6% in the sinusoidal cavity exist in human bone marrow. Hypoxia is essential for long-term HSC survival and function.…”

High Doses of Vitamin C and Leukemia: In Vitro Update

“…Overall, the available data show that hypoxia and HIF-mediated signaling play a crucial role in leukemia, and targeting HIF with specific drugs or natural inhibitors, such as Vitamin C, represents a potentially useful approach to its treatment [113].…”