title: Modeling notch signaling in normal and neoplastic hematopoiesis: global gene expression profiling in response to activated notch expression.
abstract: In normal hematopoiesis, proliferation is tightly linked to differentiation in ways that involve cell-cell interaction with stromal elements in the bone marrow stem cell niche. Numerous in vitro and in vivo studies strongly support a role for Notch signaling in the regulation of stem cell renewal and hematopoiesis. Not surprisingly, mutations in the Notch gene have been linked to a number of types of malignancies. To better define the function of Notch in both normal and neoplastic hematopoiesis, a tetracycline-inducible system regulating expression of a ligand-independent, constitutively active form of Notch1 was introduced into murine E14Tg2a embryonic stem cells. During coculture, OP9 stromal cells induce the embryonic stem cells to differentiate first to hemangioblasts and subsequently to hematopoietic stem cells. Our studies indicate that activation of Notch signaling in flk+ hemangioblasts dramatically reduces their survival and proliferative capacity and lowers the levels of hematopoietic stem cell markers CD34 and c-Kit and the myeloid marker CD11b. Global gene expression profiling of day 8 hematopoietic progenitors in the absence and presence of activated Notch yield candidate genes required for normal hematopoietic differentiation, as well as putative downstream targets of oncogenic forms of Notch including the noncanonical Wnts Wnt4 and 5A. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Ganapati
authors.forename: Hongying Tina
authors.initials: HT
authors.lastname: Tan
authors.forename: Maureen
authors.initials: M
authors.lastname: Lynch
authors.forename: Milana
authors.initials: M
authors.lastname: Dolezal
authors.forename: Sven
authors.initials: S
authors.lastname: de Vos
authors.forename: Judith C
authors.initials: JC
authors.lastname: Gasson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D053605:Leukemia Inhibitory Factor; D051881:Receptor, Notch1