Professor Taehoon Chun’s research team identified a Protein involved in Hematopoietic stem cell mobilization.
The polycomb protein that enhances stem cell mobilization by changing the bone marrow environment is now a new target for drugs against immunological disease.
▲(from the left) Professor Taehoon Chun (corresponding author, Department of Biotechnology),
Dr. Joonbeom Bae (first author) and student Sang-Pil Choi (first author).
Professor Taehoon Chun’s group in the Department of Biotechnology at the College of Life Sciences and Biotechnology discovered a new drug target capable of regulating the activity of hematopoietic stem and progenitor cells and bone marrow cancer cells.
The result of the research project supported by the Biomedical Technology Development Project (New Drug Pipeline Development) of the Ministry of Science and ICT and the National Research Foundation of Korea was published in the international journal Nature Communications on August 2.
※ Title of Article: Phc2 controls hematopoietic stem and progenitor cell mobilization from bone marrow by repressing Vcam1 expression
※ Authors: Professor Taehoon Chun (corresponding author, Korea University), Dr. Joonbeom Bae, (first author, Korea University) and Sang-Pil Choi (first author, Korea University)
The hematopoietic stem and progenitor cells (HSPCs), which are generated at the bone marrow and the origin of blood cells, regenerate various immune cells after migrating to the periphery of the body. Therefore, this trafficking of HSPCs has been a key target when developing therapeutic agents against immunological disease.
In patients who have undergone bone marrow migration, the G-CSF protein facilitates the trafficking of HSPCs from the bone marrow to the periphery for rapid immune cell regeneration, and the associated global market related to G-CSF protein amounts to 7 trillion KRW. In contrast, for patients with bone marrow cancer, the migration of the cancer cells from the bone marrow to the periphery must be inhibited to prevent the cancer metastasizing to other organs.
The research group revealed that the polycomb proteins help HSPC migration to the periphery by changing the bone marrow microenvironment. Immunodeficiency was found in mice without a thymus or spleen due to a reduction of immune cells because the migration of HSPCs to the periphery was inhibited.
The result of this study introduced the polycomb protein as a fresh target for the development of new drugs for bone marrow transplantation and bone marrow cancer to overcome the tolerance problem associated with the conventional method of directly regulating the activity of HSPCs or bone marrow cancer cells.
※ Polycomb: A protein that, through the deformation of histone protein (e.g., methylation, ubiquitination), changes the structure of chromatin, which contains genetic information, to inhibit gene expression at the modified locations.
The binding of the cell surface protein (VLA-4) to the bone marrow stromal cell protein (VCAM-1) is necessary for HSPCs to become engrafted in the bone marrow. The polycomb protein prevents the coupling of these two proteins by inhibiting the production of the bone marrow stromal cell protein. The experiment showed that the inhibition of the coupling of the two proteins by a drug that played a role similar to that of the polycomb protein resulted in the regeneration of immune cells in the bone marrow of the polycomb-deficient mice.
The method developed by the study allows for the changing of the microenvironment in the bone marrow without genetic change, and thus has the advantage of reducing the tolerance.
Professor Chun said, “This study is significant because the result laid the foundation for regulating the activity of HSPCs, which are essential for hematopoiesis, by an epigenetic method.” He also explained, “I expect that, on the basis of this result, a therapeutic agent will be developed and applied to bone marrow transplantation or bone marrow cancer patients.”
[Explanation of Terms]
1. Hematopoietic stem cell
A cell that exists in the bone marrow and has the capability of producing all blood cell types (red blood cells and white blood cells) and platelets.
2. Bone marrow stromal cell (BMSC)
A cell that interacts with the hematopoietic stem cell in the microenvironment of the bone marrow cell and provides all the elements necessary for hematopoietic stem cell activation, including their survival, differentiation, division and migration to the periphery.
3. Bone marrow transplantation (BMT)
Transplantation of the hematopoietic stem cells of donors to patients with leukemia or other rare diseases that cause immunodeficiency to regenerate the donor’s immune cells in the body of the recipient. Before transplantation of the hematopoietic stem cells of the donor to the patient, the patient’s HSPCs and mature immune cells are completely destroyed.
4. Bone marrow cancer
The most common type of leukemia, accounting for about 70% of acute leukemia. Multiple myeloma is one type of bone marrow cancer. Bone marrow cancer refers to the cancerization of HSPCs in the bone marrow, and that cancer may migrate to the periphery.
Regulation of gene expression in the absence of changes in the DNA base sequence. Epigenetics usually occurs through changes in chromatin structure regulated by DNA methylation and the deformation of histone protein. In the case of the polycomb protein, the expression of a specific gene is inhibited as the chromatin structure is changed by the methylation and ubiquitination of histone protein.
(Figure) Effect of the polycomb protein on the migration of HSPCs in the bone marrow (schematic diagram)
The binding of the VLA-4 cell surface protein, which is expressed in HSPCs, to the VCAM-1 protein, which is expressed in BMSCs, is necessary for the engraftment of HSPCs in the bone marrow. Normally the polycomb protein changes the chromatin structure by methylating and ubiquitylating a specific histone protein in the Vcam1 gene locus to inhibit the expression of the Vcam1 gene. As a result, VCAM-1 expression on the cell surface decreases, and HSPCs migrate to the periphery. However, when the function of the polycomb protein is suppressed, VCAM-1 expression on the cell surface increases and the migration of HSPCs to the periphery is inhibited.