Role of Hypoxia Induction Factor in Hematology - A Complete Guide

Introduction:

Any pathological or environmental change, internal or external to the body, induces a response from the body. Such responses that a body produces are called physiological responses. Some physiological responses are considered to be very critical and should be looked upon immediately and adeptly for efficient management of the causative factor. One such response is hypoxia of the body.

What Is Hypoxia?

Hypoxia is considered a physiological condition of the human body where there is reduced availability or deficiency of oxygen. Thus, tissues and vital organs lack oxygen for normal functioning and metabolism. A disruption in the metabolic functions of a cell due to hypoxia can cause damage and death of the cells (necrosis).

Common etiological agents associated with the causation of hypoxia are:

• High altitudes.

• Lung diseases.

• Anemia.

• Heart diseases.

What Are Hypoxia Induction Factors?

When the environment within the body is deprived of oxygen, every cell and tissue in the body tries to adapt through sophisticated mechanisms. One such mechanism is the release of hypoxia induction factors.

Hypoxia induction factors are transcription factors that help regulate the body’s response to low-oxygen environments. Transcription factors regulate a biological process by binding to a cell's DNA and modifying it. When a transcription factor binds to a particular section of DNA, it can signal to the cell's machinery to start copying the instructions for making a specific protein or block that process. A transcription factor like the hypoxia induction factor tends to perform the function of adapting to a hypoxic environment in the same way.

Hypoxia induction factors have two subunits. They are the oxygen-sensitive alpha subunit (HIF-α) and a constitutively expressed beta subunit (HIF-β). When the oxygen level is normal or optimal within the body, HIF-α subunits are hydroxylated by prolyl hydroxylase enzymes, marking them for degradation through a ubiquitin-proteasome pathway. The prolyl hydroxylase enzyme activity is inhibited when oxygen levels go below normal. So, there is an accumulation of HIF-α subunits. These accumulated HIF-α subunits translocate to the nucleus, where they dimerize with HIF-β subunits and bind to specific DNA sequences known as hypoxia-response elements in the promoter regions of target genes. Thus, the target genes are activated to perform the tasks of angiogenesis, erythropoiesis, glycolysis, cell proliferation, and apoptosis. By activating the normal cellular processes, hypoxia induction factors tend to adapt to low-oxygen conditions and survive hypoxia. Thus, they are considered master cell function regulators during hypoxic conditions.

What Is the Role of Hypoxia Induction Factor in Hematology?

Hematopoiesis:

• This hematological process is associated with forming new blood cells in the bone marrow. The hypoxia induction factor is closely related to this process as it regulates this activity. The entire process of blood cell formation occurs in the marrow of the bone. After formation, the blood cells are differentiated into different lineages to form mature blood cells like red blood cells (erythropoiesis), white blood cells, and platelets.

• The hypoxia induction factor regulates the mechanism of erythropoiesis. In a hypoxic state, a hormone called erythropoietin is stimulated by this factor. Erythropoietin hormone holds the important function of converting erythroid precursor cells to mature red blood cells. When this hormone is stimulated, immature red cells mature more. Thus, hypoxia induction factors ensure an adequate and constant supply of red blood cells to take oxygen. This can prevent serious complications of hypoxic states within the body.

• Also, hypoxia induction factors are responsible for mobilizing hematopoietic stem cells, making them available for cells that have undergone injury and require repair.

• Hypoxia induction factors also modulate the differentiation of other myeloid cells. This is achieved by producing cytokines and other growth factors (for example, granulocyte colony-stimulating factor) that are deemed necessary for differentiating the myeloid cells.

• Also, these induction factors help migrate macrophage cells and immune (phagocytic) activity. Thus, immune surveillance in the body is ensured.

Thus, the hematopoietic cells' production, proliferation, differentiation, and survival are completely ensured by hypoxia induction factors to prevent disruption of normal hematopoietic activity in hypoxic states.

Hematological Disorders:

One of the reasons for an increased incidence of hematological disorders is the dysregulation of the hypoxia induction factors.

• In anemia, red blood cell formation and differentiation (erythropoiesis) can be disrupted due to improper signaling of the hypoxia induction factors. The stimulation of erythropoietin is also impaired.

• In many individuals with polycythemia vera, mutations in genes associated with the signaling of hypoxia induction factors and production of prolyl hydroxylases are noted. These mutations lead to constitutive activation of hypoxia induction factors and increased expression of erythropoietin hormone, promoting erythrocytosis (elevated red blood cell count).

• Aberrant activation of hypoxia induction factor signaling has been implicated in the pathogenesis of various types of leukemia. Hypoxia induction factor generally promotes leukemic cell survival, proliferation (multiplication and growth), and chemotherapy resistance by upregulating genes involved in processes like glycolysis, angiogenesis, and anti-apoptotic pathways. Moreover, the bone marrow microenvironment in leukemia patients is often hypoxic, further enhancing the activity of these factors and promoting leukemic cell growth.

Thus, dysfunctional activity and signaling of the hypoxia induction factors are responsible for the increased likelihood of hematological disorders and conditions.

What Are the Therapeutic Applications of Hypoxia Induction Factors?

• The stabilizing property of the hypoxia induction factor is used to create therapies for the management of anemia. This can particularly benefit chronic kidney disease patients and erythropoietin deficiency diseases.

• Studies and research have made the successful usage of hypoxia induction factors for ischemic conditions (like myocardial infarction). In such conditions, tissue death can be prevented by promoting blood vessel formation through the action of hypoxia induction factors.

• Enhancing angiogenesis, facilitating collagen deposition, and ensuring cell migration are characteristic features of these factors. Hence, they are used to induce better wound healing.

• Hypoxia induction factor inhibitors are being investigated for use as anticancer agents (monotherapy) for managing solid tumors and hematological malignancies.

• Hypoxia induction factors are used to reduce tissue damage for the noble purpose of organ preservation during the transplantation process. This, in turn, helps in a better prognosis of organ transplantation.

Conclusion:

Understanding how hypoxia induction factors affect the body's response to low oxygen levels opens up new treatment possibilities. By targeting this factor with drugs or gene therapy, researchers hope to provide a good prognosis for patients with conditions like anemia, ischemic diseases, and cancer. Thus, hypoxia induction factors are seen as a limelight for future medicine.