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Publication : Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells.

First Author  Chiang MY Year  2013
Journal  Blood Volume  121
Issue  6 Pages  905-17
PubMed ID  23115273 Mgi Jnum  J:194558
Mgi Id  MGI:5474161 Doi  10.1182/blood-2012-03-416503
Citation  Chiang MY, et al. (2013) Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells. Blood 121(6):905-17
abstractText  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.
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