title: Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells.
abstract: The leukemia stem cell (LSC) hypothesis proposes that a subset of cells in the bulk leukemia population propagates the leukemia.We tested the LSC hypothesis in a mouse model of Notch-induced T-cell acute lymphoblastic leukemia (T-ALL) in which the tumor cells were largely CD4+ CD8+ T cells. LSC activity was enriched but rare in the CD8+ CD4 HSA(hi) immature single-positive T-cell subset. Although our murine T-ALL model relies on transduction of HSCs, we were unable to isolate Notch-activated HSCs to test for LSC activity. Further analysis showed that Notch activation in HSCs caused an initial expansion of hematopoietic and T-cell progenitors and loss of stem cell quiescence, which was followed by progressive loss of long-term HSCs and T-cell production over several weeks. Similar results were obtained in a conditional transgenic model in which Notch activation is induced in HSCs by Cre recombinase. We conclude that although supraphysiologic Notch signaling in HSCs promotes LSC activity in T-cell progenitors, it extinguishes self-renewal of LT-HSCs. These results provide further evidence for therapeutically targeting T-cell progenitors in T-ALL while also underscoring the need to tightly regulate Notch signaling to expand normal HSC populations for clinical applications.
authors.affiliation: Division of Hematology-Oncology and the University of Michigan Cancer Center, University of Michigan, Ann Arbor, MI, USA. markchia@umich.edu
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Chiang
authors.forename: Olga
authors.initials: O
authors.lastname: Shestova
authors.forename: Lanwei
authors.initials: L
authors.lastname: Xu
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D057809:HEK293 Cells; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D018398:Homeodomain Proteins; D051880:Receptors, Notch; C064658:RAG-1 protein; D005472:Fluorouracil