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Description:
This scientific session will discuss up to date knowledge on the mechanisms of genetic rescue in inherited BMF syndromes.
Dr. Jean Soulier will present new data on clonal hematopoiesis in Fanconi anemia (FA), a DNA repair disorder with chromosome instability resulting in hematopoietic stem/progenitor cell exhaustion, BMF and high-risk myeloid leukemia. Half of FA patients develop chromosome 1q gain with resulting MDM4 trisomy which downregulates the overactive p53 signaling, which can be later followed by secondary leukemia-driver alterations. Functionally, MDM4 triplication confers greater fitness to murine and human hematopoiesis, rescues inflammatory marrow failure, and drives clonal dominance in FA mouse models. He will also demonstrate how early MDM4-driven downregulation of p53 activation plays a pivotal role in FA clonal evolution.
Dr. Alyssa Kennedy will discuss clonal hematopoiesis and the specific somatic mutations that occur in the bone marrow of patients with Shwachman-Diamond Syndrome (SDS). SDS is a ribosomopathy caused by biallelic mutations in the SBDS gene. The lack of SDS protein leads to defects in ribosome maturation. Patients with SDS develop clonal hematopoiesis at an early age. The somatic mutations in SDS consist of adaptive mutations - as in EIF6 - or maladaptive mutations in TP53. Dr. Kennedy will discuss the underlying mechanism of clonal expansion in SDS and the implications of clonal hematopoiesis for surveillance.
Dr. Sushree Sahoo will introduce into the recently discovered SAMD9 and SAMD9L (SAMD9/9L) diseases, hereditary BMF conditions with a propensity for myelodysplasia with monosomy 7. Germline SAMD9/9L mutations are deemed gain-of-function mutations as their overexpression inhibits cellular growth, halts translation, and lead to cell death in a manner that is significantly higher than the wildtype protein. Many patients attain somatic genetic rescue, causing inactivation of mutant alleles and selective clonal hematopoiesis. Dr. Sahoo will elaborate on the clonal trajectories and clinical implications of rescue events in SAMD9/9L and provide an overview of the current understanding of the molecular mechanism by which SAMD9/9L mutants impair hematopoiesis.
Dr. Jean Soulier will present new data on clonal hematopoiesis in Fanconi anemia (FA), a DNA repair disorder with chromosome instability resulting in hematopoietic stem/progenitor cell exhaustion, BMF and high-risk myeloid leukemia. Half of FA patients develop chromosome 1q gain with resulting MDM4 trisomy which downregulates the overactive p53 signaling, which can be later followed by secondary leukemia-driver alterations. Functionally, MDM4 triplication confers greater fitness to murine and human hematopoiesis, rescues inflammatory marrow failure, and drives clonal dominance in FA mouse models. He will also demonstrate how early MDM4-driven downregulation of p53 activation plays a pivotal role in FA clonal evolution.
Dr. Alyssa Kennedy will discuss clonal hematopoiesis and the specific somatic mutations that occur in the bone marrow of patients with Shwachman-Diamond Syndrome (SDS). SDS is a ribosomopathy caused by biallelic mutations in the SBDS gene. The lack of SDS protein leads to defects in ribosome maturation. Patients with SDS develop clonal hematopoiesis at an early age. The somatic mutations in SDS consist of adaptive mutations - as in EIF6 - or maladaptive mutations in TP53. Dr. Kennedy will discuss the underlying mechanism of clonal expansion in SDS and the implications of clonal hematopoiesis for surveillance.
Dr. Sushree Sahoo will introduce into the recently discovered SAMD9 and SAMD9L (SAMD9/9L) diseases, hereditary BMF conditions with a propensity for myelodysplasia with monosomy 7. Germline SAMD9/9L mutations are deemed gain-of-function mutations as their overexpression inhibits cellular growth, halts translation, and lead to cell death in a manner that is significantly higher than the wildtype protein. Many patients attain somatic genetic rescue, causing inactivation of mutant alleles and selective clonal hematopoiesis. Dr. Sahoo will elaborate on the clonal trajectories and clinical implications of rescue events in SAMD9/9L and provide an overview of the current understanding of the molecular mechanism by which SAMD9/9L mutants impair hematopoiesis.