• Prof. ZHANG Ying

An Essay of erythropoietin and its role in haematology 促红细胞生成素及其在血液学中的作用

Ying ZHANG



The brief development of erythropoietin in the field of Haematology

Erythropoietin (EPO) is a hormone produced primarily by the kidneys. Its major role is to stimulate the production of red blood cells (RBCs) from bone marrow when low level of RBCs occurs. The consequence of the participation of EPO from kidneys is to have more oxygen carried in the RBCs from the lungs to the rest of the body. [here please refer to the more detailed carrier of oxygen in BRC—hemoglobin]


The discovery of erythropoietin can be traced back to one century ago when two French scholars found that the RBC production increases in normal rabbits once they were injected a small amount of plasma of anaemic rabbits. This facilitator (enzyme / protein) of the stimulating activity of RBC is later called erythropoietin(EPO) and has been widely used to treat RBC-related diseases.



The essential role of erythropoietin in the field of haematology has developed with the development of combination of medical and molecular engineering. For example, hemodialysis, a method to remove waste products from the blood, could help patients who suffer from kidneys function deterioration (in such a case, the basic function of kidneys lost without producing (sufficeint9 erythropoietin for stimulating RBC production). The combination of hemodialysis and Epo therapy could help such patients survive in the underlying diseases. Moreover, in the recent decade of studies and clinic practices, EPO Therapy has proved to be very useful in treating anaemia (a shortage of red blood cells) but also other chronic kidney disease or a wide variety of haematological disorder (i.e. multiple myeloma) and cancers (from which patients suffer anaemic from chemotherapy), by imitating the action of the hormone erythropoietin, stimulating the body to produce more red blood cells.



The Carrier of Oxygen in RBC: Hemoglobin


Hemoglobin (Hb) is the protein molecule in red blood cells. Its function is mainly to carry oxygen from the lungs to the rest of the tissues of the rest body and return CO2 from the tissues back to the lungs, and maintaining the shape of the red blood cells.


Regarding Hb’s first function, within each hemoglobin exists four protein molecules (globulin chains) that are connected to each other. Within each globulin chain contains a porphyrin compound called heme. Within each heme compound is an iron atom, being responsible for transporting O2 and CO2 in blood and the red color of blood. This structure allows hemoglobin has an oxygen-binding capacity of 1.34 mL O2 per gram which increases the total blood oxygen capacity seventy-fold compared to dissolved oxygen in blood. A healthy adult has 12 to 20 grams of hemoglobin in every 100 ml of blood.



The regulation of oxygen transportation in cells


As mentioned above, in the 1980s scientists already knew low oxygen levels increased transcription of the gene for EPO in the kidney, and accordingly boosted production of oxygen-carrying red blood cells. But how cells sense a lack of oxygen was unclear, and how cells sense oxygen and regulate it production and transportation was unclear. In 2019, three scientists (William Kaelin Jr. at the Dana-Farber Cancer Institute in Boston, Peter Ratcliffe of the University of Oxford, and Gregg Semenza of Johns Hopkins University School of Medicine in Baltimore, Maryland) received Nobel Award due to their research into how cells detect oxygen and react to hypoxia—conditions when oxygen is low in tissues.


To interpret their research, understanding the role of HIF is necessary. HIF, named as hypoxia-inducible factor, is a protein binding to the regulatory region of the EPO gene when there is little oxygen. HIF is made up of two parts: HIF-1alpha and HIF-1beta (or ARNT). Only HIF-1alpha is able to sense oxygen directly. Studies by Semenza, Ratcliffe, and Kaelin showed under normal oxygen conditions, two amino acids of the HIF-1alpha protein are chemically modified by enzymes called prolyl hydroxylases. The modified HIF-1alpha can then bind to a protein called VHL and that complex is tagged for destruction in the cell’s garbage disposal, the proteasome. Under low oxygen conditions, however, the enzymes that chemically modify HIF-1alpha become inactive. Instead of binding to VHL and being destroyed, HIF-1alpha migrates to the cell’s nucleus, where it unites with HIF-1beta and binds to certain parts of the genome, regulating transcription of hundreds of genes including the one for EPO. Kaelin found that cancer cells lacking the protein turn on hypoxia-related genes, therefore the cancer connections to this oxygen sensing system have only expanded. Some of the genes controlled by HIF are used by tumor cells to produce blood vessels to nourish themselves, others directly act on cell proliferation or metastasis. Several compounds that inhibit HIF-1alpha or the closely related HIF-2alpha are being tested in clinical trials to treat cancer patients. Drugs, for example, derived from these discoveries, roxadustat, was approved in China in 2018 for the treatment of anemia in people with chronic kidney disease.



The implications of the discovery of oxygen sense by cells is significant. First, Oxygen sensing is integral to many diseases and numerous drugs are being developed to alter the response of this system to treat everything from cancer to anemia.


Second, HIF exists in every cell of the body, not only in the nervous system, but also the blood vessels, the immune system. When immune cells invade inflamed tissue where usually hypoxic is a default, HIF could be active to help generate more oxygen.







Reference


H. E. Nicholson et al., "HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species," Science Signaling 12, 601 (01 Oct 2019)

N. Masson et al., "Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants," Science 365, 6448 (05 Jul 2019)

A. A. Chakraborty et al., "Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate," Science 363, 6432 (15 Mar 2019)

A. A. Chakraborty et al., "HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase," Science Translational Medicine 9, 398 (12 Jul 2017)

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