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) is a devastating blood disorder, affecting children and adults, caused by immune attack on the bone marrow bone marrow: The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow. . Factors that determine recovery, relapse, and transformation to myelodysplasia in aAA remain poorly defined, and there is a dearth of studies in pediatric patients. Emerging data suggest that mutations in the bone marrow and in the pathogenic immune cells contribute to disease evolution and relapse. To study this, I will employ cutting-edge genomic techniques to characterize pathogenic mutations in aAA. These studies will improve treatment of patients with pediatric AA by allowing early detection of clonal evolution and disease progression.
In the first year of this project we used cutting-edge genetic techniques to look for new mutations and larger genetic aberrations in the
bone marrow
bone marrow:
The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow.
of an initial cohort of approximately thirty
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…
patients at the Children’s Hospital of Philadelphia and the University of Pennsylvania. Our findings showed that the majority of aplastic anemia patients, including children, have detectable genetic changes in their bone marrow. These changes are not present in the patient’s skin, indicating that these mutations are not inherited, but rather emerge in the bone marrow in the course of the disease. New mutations can be detected as early as one year after diagnosis. The most common mutations in our initial study were those that lead to the development of
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…
and those that cause the loss of immune recognition. The mutations were present in a significant portion of early blood cells, indicating that in most patients, a substantial part of their blood production comes from the progeny of a single cell that acquired these genetic changes. Among the mutations identified in the study, many were in genes involved in immune response and cell growth. Based on their findings, we hypothesize that a patient’s response to treatment and their overall disease course can be affected by individual differences in the genetic make-up of their bone marrow.
In the second year of this project, we plan to validate these preliminary results in a larger number of patients. We will also follow the patients’ genetic changes over time to determine the impact of acquired mutations on prognosis and patients’ recovery. Our long-term goal is to use the knowledge of the genetic make-up of an individual patient’s bone marrow to improve the diagnosis and disease surveillance of aplastic anemia patients. We hope results of our studies will pave way for personalized treatment strategies, bringing Precision Medicine to the field of aplastic anemia. These studies would not have been possible without the generous support from the AA&MDS International Foundation.
Summary: 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 a life-threatening blood disorder, characterized by the inability of a patient’s bone marrow bone marrow: The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow. to produce sufficient blood cells for normal life. The most common form is caused by the patient’s own immune system attacking early blood cells, leading to an empty bone marrow and dangerously low blood counts. It has long been observed that patients with acquired aplastic anemia frequently develop other blood disorders, which emerge from an expansion of blood cells carrying a genetic defect (so called “clonal blood disorders”)—such as 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… or myelodysplastic syndrome. My research is aimed at understanding of the genetic changes that can arise in the bone marrow of patients with aplastic anemia, and of how they affect the patients’ prognosis and treatment outcomes.
Progress Report: To investigate the presence of acquired mutations and other genetic aberrations in aplastic anemia, we used cutting edge genetic techniques to study the bone marrow of fifty aplastic anemia patients. Our findings show that approximately 70% of aplastic anemia patients, including 60% of children, have detectable mutations in their bone marrow. These changes are not present in the patient’s skin DNA, indicating that the patients were not born with these mutations and also cannot pass them on to their children. Rather, these mutations emerged in the course of the disease in the patients’ bone marrow in response to the immune attack. New mutations can be detected as early as one year after diagnosis. The most common mutations are those that lead to the development of Paroxysmal Nocturnal Hemoglobinuria and those that allow the cells to escape immune recognition through loss of Human Leukocyte Antigen Human Leukocyte Antigen: (LEW-kuh-site ANT-i-jun) One of a group of proteins found on the surface of white blood cells and other cells. These antigens differ from person to person. A human leukocyte antigen test is done before a stem cell transplant to closely match a donor and a recipient. Also called HLA. (HLA) genes. The mutations were present in a significant portion of early blood cells, indicating that in most patients, a substantial part of their blood production comes from the progeny of a single cell that acquired these genetic changes. Based on our data findings, we hypothesize that a patient’s response to treatment and their overall disease course can be affected by individual differences in the genetic make-up of their bone marrow. Our ongoing studies evaluate the patients’ genetic changes over time to determine the impact of acquired mutations on recovery and long-term prognosis. Our long-term goal is to use the knowledge of the genetic make-up of an individual patient’s bone marrow to improve the diagnosis and disease surveillance of aplastic anemia patients. We hope results of our studies will pave way for personalized treatment strategies, bringing Precision Medicine to the field of aplastic anemia. These studies would not have ….been possible without the generous support from the AA&MDS International Foundation.