denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Hematology Disease Topics & Pathways:
apoptosis, Diseases, Genetic Disorders, B-Cell Lymphoma, Biological Processes, immunodeficiency, immune cells, Immune Disorders, Cell Lineage, Lymphoid Malignancies, Clinically relevant, genomics, Proliferative disorders, immune mechanism, molecular interactions, pathogenesis, pathways, signal transduction
Description:
Over the last 20 years there has been an exponential rise in the identification of inborn errors of immunity, now numbering >400 monogenetic defects. While the classical presentation of these diseases is recurrent and persistent infections in a young child, the uncovering of the genetic underpinnings of these fascinating diseases has led to unexpected roles for these genes in immune dysregulation, hematopoiesis, and malignancy. Furthermore, hypomorphic variants in genes traditionally thought to affect only children may manifest as milder or atypical disease in adults. The investigation of patients with inborn errors of immunity thus provide unique insights into biology, immunology, and molecular mechanisms of disease. In this series of talks, these dynamic speakers will shed some light on the complex and tightly regulated interplay between a dysregulated immune system and abnormal hematopoiesis and malignant transformation. Drs. Lucas and Snow will discuss the roles of PI3K subunits and CARMA proteins respectively, both gain and loss-of-function variants, in lymphocyte biology and lymphomagenesis. Drs. Latour and Holland will discuss the roles of IKZF1 and GATA2 respectively in immune cell development, function, malignancy.
Dr. Carrie Lucas will describe Activated PI3K-delta Syndrome (APDS) patients with germline gain-of-function mutations in the genes encoding the leukocyte-restricted PI3Kdelta subunits p110delta and p85alpha and discuss their similarity to oncogenic mutations. These patients have immunodeficiency, autoimmunity, and lymphoproliferative disease, and have recently been successfully treated with targeted therapy specifically inhibiting the PI3Kdelta complex. She will then transition to recent work on a new disorder termed ‘Inactivated PI3K-gamma Syndrome’ (IPGS), caused by loss-of-function mutations in the gene encoding the p110gamma PI3K subunit. This rare disease has features of immunopathology and immunodeficiency, including features not previously expected from knockout mice. The p110gamma kinase is being inhibited in clinical trials to boost myeloid cell responses in cancer, as such, Dr. Lucas will describe how her lab’s findings in rare disease illuminate roles for this kinase directly in humans.
Dr. Andrew Snow will provide an overview of primary immune regulation disorders associated with mutations in CARMA proteins and their associated signaling partners, BCL10 and MALT1. Particular emphasis will be paid to the broad spectrum of immune diseases associated with mutations in CARMA1 (CARD11). He will discuss underlying molecular mechanisms explaining lymphocyte signaling defects and associated clinical phenotypes, including predisposition to lymphoma. Current and novel therapeutic strategies for CARMA-related immune disorders will also be briefly covered.
Dr. Sylvain Latour will first discuss the biology of the transcription factor IKZF1, its role in development of immune cells, normal hematopoiesis, and lymphomagenesis associated with somatic mutations in IKZF1. He will then focus on work from his laboratory delineating the impact of germinal mutations in IKZF1 in humans on lymphocyte development and function, contrasting the effect of loss of function, dominant negative variants and novel recently identified mutations. He will further discuss the underlying molecular and pathophysiological mechanisms of these different mutations and their association with clinical phenotypes.
Dr. Steven Holland will review the varied phenotypes and presentations of in GATA2. There are broad genotype/phenotype associations as well as variations in penetrance and expression. With the recruitment, longitudinal follow up and treatment of large cohorts of patients, some general aspects of management and successful transplantation can be derived. The biology of GATA2 and its many roles in blood, immune cell and lymphatic development and function have been exciting areas of investigation. He will review current concepts of GATA2 in myelodysplasia and myeloid malignancy, as well as some molecular mechanisms of GATA2 deficiency in allergic, rheumatologic and immunodeficiency diseases.
Dr. Carrie Lucas will describe Activated PI3K-delta Syndrome (APDS) patients with germline gain-of-function mutations in the genes encoding the leukocyte-restricted PI3Kdelta subunits p110delta and p85alpha and discuss their similarity to oncogenic mutations. These patients have immunodeficiency, autoimmunity, and lymphoproliferative disease, and have recently been successfully treated with targeted therapy specifically inhibiting the PI3Kdelta complex. She will then transition to recent work on a new disorder termed ‘Inactivated PI3K-gamma Syndrome’ (IPGS), caused by loss-of-function mutations in the gene encoding the p110gamma PI3K subunit. This rare disease has features of immunopathology and immunodeficiency, including features not previously expected from knockout mice. The p110gamma kinase is being inhibited in clinical trials to boost myeloid cell responses in cancer, as such, Dr. Lucas will describe how her lab’s findings in rare disease illuminate roles for this kinase directly in humans.
Dr. Andrew Snow will provide an overview of primary immune regulation disorders associated with mutations in CARMA proteins and their associated signaling partners, BCL10 and MALT1. Particular emphasis will be paid to the broad spectrum of immune diseases associated with mutations in CARMA1 (CARD11). He will discuss underlying molecular mechanisms explaining lymphocyte signaling defects and associated clinical phenotypes, including predisposition to lymphoma. Current and novel therapeutic strategies for CARMA-related immune disorders will also be briefly covered.
Dr. Sylvain Latour will first discuss the biology of the transcription factor IKZF1, its role in development of immune cells, normal hematopoiesis, and lymphomagenesis associated with somatic mutations in IKZF1. He will then focus on work from his laboratory delineating the impact of germinal mutations in IKZF1 in humans on lymphocyte development and function, contrasting the effect of loss of function, dominant negative variants and novel recently identified mutations. He will further discuss the underlying molecular and pathophysiological mechanisms of these different mutations and their association with clinical phenotypes.
Dr. Steven Holland will review the varied phenotypes and presentations of in GATA2. There are broad genotype/phenotype associations as well as variations in penetrance and expression. With the recruitment, longitudinal follow up and treatment of large cohorts of patients, some general aspects of management and successful transplantation can be derived. The biology of GATA2 and its many roles in blood, immune cell and lymphatic development and function have been exciting areas of investigation. He will review current concepts of GATA2 in myelodysplasia and myeloid malignancy, as well as some molecular mechanisms of GATA2 deficiency in allergic, rheumatologic and immunodeficiency diseases.