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Hematology Disease Topics & Pathways:
Research, Fundamental Science, Genomics, Biological Processes
Description:
Single cell multi-omic studies of normal and malignant hematopoiesis highlight how hematology remains an ideal testing ground for technologic innovation. Continued advancements in single cell sequencing and the analysis of these complex datasets have informed functional experiments that have enabled the field to improve our understanding of hematopoietic stem cell behavior and myeloid differentiation in response to aging, inflammation, and malignant transformation. This session will showcase innovative transcriptomic and functional genomic studies of the pathways that govern myeloid differentiation in response to aging, inflammation, and malignancy.
Dr. Laurenti will focus on how mutations at the DNMT3A R882 hotspot impact differentiation into mature myeloid cell types in steady-state and inflammatory contexts. She will report evidence implicating neutrophils in an inflammatory vicious circle triggered by the acquisition of DNMT3A R882 mutations in hematopoietic stem cells. She will also discuss findings which could contribute to explain the high risk of leukemia associated with DNMT3A R882 mutations.
Dr. Dick will explore how aging and inflammatory conditions impact myelopoiesis and pre-leukemic clonal expansions. He will focus on the identification of HSC-inflammatory memory (HSC-iM), a new HSC population that remembers prior inflammatory stress and adapts to chronic inflammation through dormancy and impaired differentiation output. He will present evidence that selective advantage of CH-mutant HSCs arise as a consequence of relieving the increased dormancy and decreased differentiation output of HSC-iM. Through scRNA/ATAC analysis, combined with novel lineage trace analysis, evidence will be presented that HSC-iM transmit their activated programs to their myeloid progeny resulting in their pro-inflammatory properties.
Dr. Klein will examine natural variation in human bone marrow biopsies from over 70 individuals with a representation of ages, genders and ethnicities. He will report on the stereotyped covariation identified between certain progenitor and mature cell type frequencies, and present evidence of both constrained and divergent gene expression programs across the 70 individuals. He will also discuss how the tumor microenvironment can impact the function of mature myeloid cells.
Dr. Laurenti will focus on how mutations at the DNMT3A R882 hotspot impact differentiation into mature myeloid cell types in steady-state and inflammatory contexts. She will report evidence implicating neutrophils in an inflammatory vicious circle triggered by the acquisition of DNMT3A R882 mutations in hematopoietic stem cells. She will also discuss findings which could contribute to explain the high risk of leukemia associated with DNMT3A R882 mutations.
Dr. Dick will explore how aging and inflammatory conditions impact myelopoiesis and pre-leukemic clonal expansions. He will focus on the identification of HSC-inflammatory memory (HSC-iM), a new HSC population that remembers prior inflammatory stress and adapts to chronic inflammation through dormancy and impaired differentiation output. He will present evidence that selective advantage of CH-mutant HSCs arise as a consequence of relieving the increased dormancy and decreased differentiation output of HSC-iM. Through scRNA/ATAC analysis, combined with novel lineage trace analysis, evidence will be presented that HSC-iM transmit their activated programs to their myeloid progeny resulting in their pro-inflammatory properties.
Dr. Klein will examine natural variation in human bone marrow biopsies from over 70 individuals with a representation of ages, genders and ethnicities. He will report on the stereotyped covariation identified between certain progenitor and mature cell type frequencies, and present evidence of both constrained and divergent gene expression programs across the 70 individuals. He will also discuss how the tumor microenvironment can impact the function of mature myeloid cells.