Overexpression of the Notch target genes Hes in vivo induces lymphoid and myeloid alterations

Oncogene (2002) 21, 3855 3863 2002 Nature Publishing Group All rights reserved 0950 9232/02 $25.00www.nature.com/oncOverexpression of the Notch target genes Hes in vivo induces lymphoid and

myeloid alterationsShin Kawamata1,3, Changchun Du1, Kaijun Li2 and Catherine Lavau*,1,41SyStemix Inc. 3155 Porter Dr. Palo Alto, California, CA 94304, USA; 2Departments of Pathology and Developmental Biology,

Stanford University School of Medicine, Stanford, California, CA 94305, USATo examine the eects of Notch signaling on hematopoiesis, we transplanted mice with progenitors transduced

with a constitutively active form of Notch1 (Notch1IC)

or the Notch1 target genes Hes. Notch1IC-transduced

cells induce T cell tumors and cannot generate B

lymphocytes in vivo. Hes-transplanted mice remained

healthy but cells transduced with Hes1 or Hes5 were

partially impaired in their ability to dierentiate into B

cells. Both Hes1 and Hes5 were upregulated in the BM

of Notch1IC mice and their ability to interfere with the

transcriptional activity of E2A in a reporter assay was

comparable to that of Notch1IC. This suggests that the

inhibition of B cell development in the Notch1IC-

transduced cells could be mediated by the interference

of HES1/HES5 proteins with E2A. Hes1-, Hes5- and

Notch1IC-transduced bone marrow cells cultured ex vivo

in a colony forming assay in the presence of cytokines

that promote myeloid dierentiation remained very

immature, indicating that the myeloid potential of these

bone marrow cells was altered. Thymocytes overexpressing Hes1, Hes5 or Notch1IC matured normally into

CD4 and CD8 single positive cells in vivo. Altogether

our data suggest that Notch1IC induces T cell tumors

independently of Hes genes but that its interference with

lymphoid B and myeloid maturation is partly mediated

by Hes1 and Hes5.Oncogene (2002) 21, 3855 3863. DOI: 10.1038/sj/

onc/1205487Keywords: Hes; Notch; B cells; hematopoiesisIntroductionNotch family genes encode cell surface receptors found

in a variety of organisms including Drosophila, Xenopus

and higher vertebrates. The Notch signaling pathway is

involved in a broad range of cell fate decisions and its

function in Drosophila morphogenesis has been well

documented (Artavanis-Tsakonas et al., 1995, 1999).

The knowledge accumulated in this eld has provided

the framework to explore the function of Notch

signaling in mammalian hematopoiesis (Osborne and

Miele, 1999). Several in vivo studies have shown that

Notch aects cell fate decisions in lymphoid development. Transgenic mice models in which expression of