講師１ 国立国際医療研究センター研究所 生体恒常性プロジェクト・プロジェクト長
講師２ Associate Professor of Medicine Chief, Division of Hematology Institute for Stem Cell Biology and Regenerative Medicine Stanford University School of Medicine
1.Functional alteration of hematopoietic stem cell niche during aging
2.Stem Cells and Human AML
1.Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. A particular gap is our understanding of the age-related alteration of HSC niche, which bridges environmental cues to HSC aging. Recent studies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors required for HSC integrity at steady state and in stress. To approach aging-related alteration in HSC niche from a metabolic perspective, we recently took advantage of technical developments in metabolomics and in vivo imaging. In this mini-symposium, I will address the environmental regulation that tunes arrival of HSC to bone marrow after transplantation and its alteration during aging.
2.AML develops from the sequential acquisition of multiple mutations in a single lineage of cells. These mutations initially occur in HSCs, termed pre-leukemic HSCs, and are enriched in genes involved in regulation of the epigenome. The pre-leukemic cells acquire additional mutations, often in genes involved in proliferation, resulting in development of AML. Stratification of a cohort of AML patients into high or low pre-leukemic HSC groups demonstrated that the high group had much worse overall and relapse-free survival, indicating that the presence of pre-leukemic HSC may be critical for clinical outcomes. In bulk AML, sequencing studies demonstrated that most cases harbor multiple subclones with a complex evolutionary structure. These subclones potentially exhibit distinct features including leukemia stem cell properties, clonal dominance, and responses to chemotherapy and targeted agents. Isolating and investigating these subclones is essential to understanding their properties, and is facilitated by a novel humanized ossicle xenotransplantation model, single cell methods, and CRISPR/Cas9 engineering of normal and leukemic cells. Eventually, all subclones must be targeted in order to improve long-term outcomes and for potential cures in AML. Notably, mutation-specific targeted agents have the potential to improve outcomes in AML. Several approaches were employed to identify mutation-specific vulnerabilities including epigenomic profiling, computational approaches, and metabolomic profiling. Several targets were validated through genetic and/or pharmacologic modulation in primary AML cells and xenograft models, making them strong candidates for therapeutic development.