Acquired bone marrow failure bone marrow failure: A condition that occurs when the bone marrow stops making enough healthy blood cells. The most common of these rare diseases are aplastic anemia, myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Bone marrow failure can be acquired (begin any time in life) or can be… diseases include myelodysplastic syndrome (MDS), acquired aplastic anemia aplastic anemia: (ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells - red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most… (AA), and paroxysmal nocturnal hemoglobinuria hemoglobinuria: (hee-muh-gloe-buh-NYOOR-ee-uh) The presence of hemoglobin in the urine. (PNH). PNH is a clonal disorder originating from a multipotent hematopoietic stem cell (HSC) acquiring a PIG-A gene mutation mutation: Any change or alteration in a gene. A mutation may cause disease or may be a normal variation. Paroxysmal nocturnal hemoglobinuria (PNH) occurs because of a mutation in the PIG-A gene of a single stem cell in the bone marrow. . PIG-A mutations lead to the absence of glycosylphosphatidylinositol-anchor proteins (GPI-AP), which contributes to many manifestations of PNH. About 25% of MDS patients and 60% of AA patients also harbor small populations of PNH-like cells (0.01-10%). It was observed that: 1) 10-20% of AA patients harboring PNH-like cells eventually transform into PNH, but MDS patients seldom evolve to PNH; 2) AA patients harboring PNH-like cells may have a better response to immunosuppressive therapy immunosuppressive therapy: Immunosuppressive drug therapy lowers your body's immune response. This prevents your immune system from attacking your bone marrow, allowing bone marrow stem cells to grow, which raises blood counts. For older patients with acquired aplastic anemia, immunosuppressive drug therapy is the… ; 3) PIG-A mutation significantly increased in some human cell lines with genomic instability. However, the clinical significances of these PNH-like cells in MDS patients and AA patients are still unclear. Our preliminary data from a pilot study showed that PIG-A mutations in AA arise from multipotent HSC; PIG-A mutations in MDS are initiated at progenitor level and are transient. The PIG-A mutation frequency in MDS patients harboring PNH-like cells were 10 to 100 times higher than healthy controls. Those MDS patients harboring PNH-like cells rapidly transformed into acute myelogenous leukemia. This AA&MDS Research Grant will allow us to test our hypotheses that 1) PIG-A mutations in MDS arise from progenitors and PIG-A mutations in AA arise from multipotent HSC, this may explain why AA often evolves into PNH, but MDS seldom transform into PNH; 2) PIG-A mutant cells in MDS is a marker of genomic instability and may predict a risk of leukemic transformation. This AA&MDS Research Grant will provide us much needed fund to further explore the clinical significances of those small populations of PNH-like cells in acquired bone marrow failure diseases.
Bone marrow Bone marrow: The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow. is a sponge-like tissue inside the bones. Most blood stem cells stem cells: Cells in the body that develop into other cells. There are two main sources of stem cells. Embryonic stem cells come from human embryos and are used in medical research. Adult stem cells in the body repair and maintain the organ or tissue in which they are found. Blood-forming (hemapoietic) stem… sit in bone marrow and are capable to differentiate differentiate: To become distinct or specialized. In the bone marrow, young parent cells (stem cells) develop, or differentiate, into specific types of blood cells (red cells, white cells, platelets). into red blood cells, white blood cells, and platelets. Bone marrow failure Bone marrow failure: A condition that occurs when the bone marrow stops making enough healthy blood cells. The most common of these rare diseases are aplastic anemia, myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Bone marrow failure can be acquired (begin any time in life) or can be… occurs when stem cells are suppressed or damaged. Diseases such as myelodysplastic syndrome (MDS), acquired aplastic anemia anemia: (uh-NEE-mee-uh) A condition in which there is a shortage of red blood cells in the bloodstream. This causes a low red blood cell count. Symptoms of anemia are fatigue and tiredness. , and paroxysmal nocturnal hemoglobinuria paroxysmal nocturnal hemoglobinuria: (par-uk-SIZ-muhl nok-TURN-uhl hee-muh-gloe-buh-NYOOR-ee-uh) A rare and serious blood disease that causes red blood cells to break apart. Paroxysmal means sudden and irregular. Nocturnal means at night. Hemoglobinuria means hemoglobin in the urine. Hemoglobin is the red part of red blood cells. A… (PNH) are acquired bone marrow failure diseases. PNH arises from a stem cell that acquires PIG-A gene PIG-A gene: The gene that is in charge of making a protective shield of proteins on normal red blood cells. Paroxysmal nocturnal hemoglobinuria (PNH) occurs because of a change (mutation) in the PIG-A gene of a single stem cell in the bone marrow. mutation mutation: Any change or alteration in a gene. A mutation may cause disease or may be a normal variation. Paroxysmal nocturnal hemoglobinuria (PNH) occurs because of a mutation in the PIG-A gene of a single stem cell in the bone marrow. . PIG-A mutation further interferes with biosynthesis of an important cell surface molecule called glycosylphosphatidylinositol (GPI) and make cells vulnerable to complement attack. Acquired aplastic anemia aplastic anemia: (ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells - red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most… is usually caused by an immune attack on bone marrow stem cells, which makes bone marrow unable to produce enough red blood cells, white blood cells, and platelets. Immunosuppressive therapy Immunosuppressive therapy: Immunosuppressive drug therapy lowers your body's immune response. This prevents your immune system from attacking your bone marrow, allowing bone marrow stem cells to grow, which raises blood counts. For older patients with acquired aplastic anemia, immunosuppressive drug therapy is the… is highly effective in treating patients with aplastic anemia. MDS is also a disease in which the damaged bone marrow stem cells fail to generate enough healthy blood cells. Because of their common clinical presentation, it is often hard to distinguish these disorders. For example, many patients with MDS and aplastic anemia also contain small populations of PNH-like cells in their blood. Moreover, 0.002% white blood cells in healthy individual are PNH-like cells; however, these PNH-like cells develop from more mature cells called progenitors, which are not able to reproduce themselves and therefore do not cause disease.
It has been found that some aplastic anemia can transform to PNH with time, and both PNH and aplastic anemia can progress to MDS, but MDS almost never leads to aplastic anemia or PNH. However, the clinical significances of these small PNH-like cells in MDS and aplastic anemia are still unclear. The goal of this project is to understand the relevance of PIG-A mutation in MDS patients and aplastic anemia patients, and to explore unique clinical implications of these small PNH-like cell populations in managing patients and in predicting disease progression/transformation. Our preliminary data suggest that the PIG-A mutations that occur in aplastic anemia are similar to those occurring in PNH in that they arise from stem cells. In contrast, the PIG-A mutations that occur in MDS arising from progenitors, similar to those found in healthy persons. This likely explains why MDS patients seldom, if ever, evolve into PNH. It suggests that finding a small PNH-like cell population in MDS patients is not a reliable surrogate for needing immunosuppressive therapy. In addition, the novel assays we have developed to detect PIG-A mutations may help distinguish MDS from aplastic anemia. More importantly, our preliminary data reveal that harboring small population of PNH-like cells in MDS may be a marker of genomic instability and may predict leukemic transformation. We are working hard to recruit more eligible patients to verify those preliminary results. We are expecting to translate those research findings into a clinical trial clinical trial: A type of research study that tests how a drug, medical device, or treatment approach works in people. There are several types of clinical trials. Treatment trials test new treatment options. Diagnostic trials test new ways to diagnose a disease. Screening trials test the best way to detect a… in the near future.
It was a very exciting year working on this project. We are looking forward moving into the second year of this study.
Jeffrey J. Pu, MD, Ph.D. is an assistant professor of medicine at the Penn State Hershey Cancer Institute and Penn State College of Medicine. Prior to this position, Dr. Pu was a senior clinical/research fellow of Hematology at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins University. He also did an NIH-supported experimental hematology fellowship and a clinical transfusion medicine/blood banking fellowship at the Lindsley F. Kimball Research Institute of New York Blood Center after finishing an internal medicine residency at Mount Sinai School of Medicine.
Dr. Pu received his Ph.D. from New York Medical College in New York and his MD from Shanghai Jiao Tong University School of Medicine in Shanghai. As a physician-scientist Dr. Pu’s research interests include hematopoiesis hematopoiesis: (hi-mat-uh-poy-EE-suss) The process of making blood cells in the bone marrow. and stem cell biology. He is currently focusing on bone marrow failure bone marrow failure: A condition that occurs when the bone marrow stops making enough healthy blood cells. The most common of these rare diseases are aplastic anemia, myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Bone marrow failure can be acquired (begin any time in life) or can be… disease translational research, especially the relevance of Glycosylphosphatidylinositol (GPI)-deficient cell population in patients with acquired bone marrow failure diseases. Dr. Pu is a board certified physician.