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Hematology Disease Topics & Pathways:
Research, Acquired Marrow Failure Syndromes, autoimmune disorders, Fundamental Science, clinical trials, adult, Clinical Practice (Health Services and Quality), Bone Marrow Failure Syndromes, Translational Research, epidemiology, CHIP, Workforce, Genetic Disorders, genomics, Aplastic Anemia, Combination therapy, Clinical Research, Diversity, Equity, and Inclusion (DEI) , hematopoiesis, Paroxysmal Nocturnal Hemoglobinuria, pediatric, Diseases, Immune Disorders, immune mechanism, Therapies, immunology, therapy sequence, Adverse Events, young adult , Biological Processes, Myeloid Malignancies, Technology and Procedures, Study Population, Human, pathogenesis, omics technologies
Description:
Bone marrow failure (BMF) in aplastic anemia (AA) is due to loss of hematopoietic stem cells (HSCs), which in turn, is caused by deranged immunity and inflammation. Somatic mutations in Hla or Piga genes can lead to immune escape, while other clones involving a range of myeloid cancer genes can also emerge, presumably due to a combination of genetic drift and selection. This session will highlight recent cutting-edge research deciphering pathways by which dysimmunity, HSCs defect, and mutant clones can dynamically shape the course of the disease, spontaneously or in response to both immuno-suppressive and eltrombopag therapy.
Dr. Neal Young will show that our understanding of the immune pathophysiology of marrow failure has been deepened by new technologies—single cell ‘omics; new diseases—VEXAS; and new theories—evolutionary biology applied to somatically mutated clones. Sequencing of RNA of single cells combined with time-of-flight cytometry has allowed deep examination of aplastic anemia marrow cells pre- and post-therapy. Somatically mutated hematopoietic targets evade immune attack and survive regenerative stress, and in effector lymphocytes, propagate pathophysiologic immunity. In VEXAS, acquired mutations in a ubiquitylation gene cause hyperinflammatory rheumatologic diseases, and immune activation originates to the hematopoietic stem and progenitor cells. Modern Darwinian principles have yet to be fully applied to “benign” diseases arising in hematopoietic cells and across a wide range of human tissues.
Dr. Daria Babushok will describe the characteristics of clonal hematopoiesis in aplastic anemia, focusing on frequent somatic mutations in Human Leukocyte Antigen (HLA) Class I genes. Dr. Babushok will discuss the genetic mechanisms of HLA Class I loss, and the disproportionate frequency of mutations targeting specific HLA-A and B alleles linked to aplastic anemia pathogenesis. She will review the role and relative pathogenicity of HLA Class I alleles in predisposing to aplastic anemia and will also examine the impact of high pathogenicity alleles on clinical outcomes of aplastic anemia patients.
Dr. Austin Kulasekararaj will describe the current understanding and knowledge about somatic mutations in acquired aplastic anemia. Besides discussing the dynamics of clonal hematopoiesis during the disease course and its impact with both immunosuppressive therapy and eltrombopag, Dr. Kulasekararaj will review the mechanisms of oligoclonal hematopoiesis and their impact on response to treatment. Lastly, He will examine the impact of eltrombopag (both in treatment naïve and relapsed/refractory aplastic anemia) in high-risk clonal evolution and malignant transformation to Myelodysplastic syndrome and Acute Myeloid Leukemia.
Dr. Neal Young will show that our understanding of the immune pathophysiology of marrow failure has been deepened by new technologies—single cell ‘omics; new diseases—VEXAS; and new theories—evolutionary biology applied to somatically mutated clones. Sequencing of RNA of single cells combined with time-of-flight cytometry has allowed deep examination of aplastic anemia marrow cells pre- and post-therapy. Somatically mutated hematopoietic targets evade immune attack and survive regenerative stress, and in effector lymphocytes, propagate pathophysiologic immunity. In VEXAS, acquired mutations in a ubiquitylation gene cause hyperinflammatory rheumatologic diseases, and immune activation originates to the hematopoietic stem and progenitor cells. Modern Darwinian principles have yet to be fully applied to “benign” diseases arising in hematopoietic cells and across a wide range of human tissues.
Dr. Daria Babushok will describe the characteristics of clonal hematopoiesis in aplastic anemia, focusing on frequent somatic mutations in Human Leukocyte Antigen (HLA) Class I genes. Dr. Babushok will discuss the genetic mechanisms of HLA Class I loss, and the disproportionate frequency of mutations targeting specific HLA-A and B alleles linked to aplastic anemia pathogenesis. She will review the role and relative pathogenicity of HLA Class I alleles in predisposing to aplastic anemia and will also examine the impact of high pathogenicity alleles on clinical outcomes of aplastic anemia patients.
Dr. Austin Kulasekararaj will describe the current understanding and knowledge about somatic mutations in acquired aplastic anemia. Besides discussing the dynamics of clonal hematopoiesis during the disease course and its impact with both immunosuppressive therapy and eltrombopag, Dr. Kulasekararaj will review the mechanisms of oligoclonal hematopoiesis and their impact on response to treatment. Lastly, He will examine the impact of eltrombopag (both in treatment naïve and relapsed/refractory aplastic anemia) in high-risk clonal evolution and malignant transformation to Myelodysplastic syndrome and Acute Myeloid Leukemia.