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Description:
Inherited and acquired bone marrow failure disorders are associated with an increased risk of myeloid malignancies. Treatment of MDS or AML is challenging for these patients due to both malignancy resistance and toxicities from disease co-morbidities. An understanding of the biologic mechanisms driving bone marrow failure and clonal evolution would inform rational surveillance strategies and provide opportunities for leukemia interception. This session will present cutting-edge advances in the understanding of the molecular mechanisms driving marrow failure and clonal evolution in three different germline genetic leukemia predisposition disorders. Clinical implications for surveillance and therapeutics will be discussed.
Dr. Leighton Grimes will discuss severe congenital neutropenia, which is caused by inherited and de novo mutations leading to a profound block in neutrophil granulopoiesis. Dr. Grimes will present insights gleaned using mouse models of severe congenital neutropenia. The successive cell states encountered during normal neutrophil granulopoiesis will be described. Differential single cell gene expression and chromatic patterns in mutant cells assigned to wild type cell states via comparative genomics will be presented. These studies highlight the dominance of cell state in integrating the effects of mutations and therapy, and illustrate cell-state-specific effects of mutations, with direct consequences for attempts to repair defects.
Dr. Coleman Lindsley will discuss insights from Shwachman-Diamond syndrome, a disorder characterized by impaired ribosome assembly. Dr. Lindsley will present novel somatic mutation pathways driven by the germline genetic background. These studies show how germline genetic context together with the cell-specific somatic mutational context determine the functional contribution of a somatic mutation to relative cell fitness, selection, and malignant potential. These studies identify adaptive and maladaptive pathways of clonal expansion in response to a germline genetic selective pressure and provide a mechanistic rationale for clinical surveillance.
Dr. Paula Rio will discuss clonal tracking following gene therapy to treat Fanconi anemia, a disorder of DNA repair. She will provide an update on a phase I/II gene therapy trial that has shown successful engraftment and proliferative advantage of corrected HSCs in FA-A patients in the absence of conditioning. Dr. Rio will discuss the engraftment, clonal tracking and phenotypic correction of HSCs in these initial patients with up to 3 years of follow up.
Dr. Leighton Grimes will discuss severe congenital neutropenia, which is caused by inherited and de novo mutations leading to a profound block in neutrophil granulopoiesis. Dr. Grimes will present insights gleaned using mouse models of severe congenital neutropenia. The successive cell states encountered during normal neutrophil granulopoiesis will be described. Differential single cell gene expression and chromatic patterns in mutant cells assigned to wild type cell states via comparative genomics will be presented. These studies highlight the dominance of cell state in integrating the effects of mutations and therapy, and illustrate cell-state-specific effects of mutations, with direct consequences for attempts to repair defects.
Dr. Coleman Lindsley will discuss insights from Shwachman-Diamond syndrome, a disorder characterized by impaired ribosome assembly. Dr. Lindsley will present novel somatic mutation pathways driven by the germline genetic background. These studies show how germline genetic context together with the cell-specific somatic mutational context determine the functional contribution of a somatic mutation to relative cell fitness, selection, and malignant potential. These studies identify adaptive and maladaptive pathways of clonal expansion in response to a germline genetic selective pressure and provide a mechanistic rationale for clinical surveillance.
Dr. Paula Rio will discuss clonal tracking following gene therapy to treat Fanconi anemia, a disorder of DNA repair. She will provide an update on a phase I/II gene therapy trial that has shown successful engraftment and proliferative advantage of corrected HSCs in FA-A patients in the absence of conditioning. Dr. Rio will discuss the engraftment, clonal tracking and phenotypic correction of HSCs in these initial patients with up to 3 years of follow up.