TY - JOUR
T1 - Expression of AML1-d, a short human AML1 isoform, in embryonic stem cells suppresses in vivo tumor growth and differentiation
AU - Aziz-Aloya, Revital Ben
AU - Levanon, Ditsa
AU - Karn, Heather
AU - Kidron, Debora
AU - Goldenberg, Dalia
AU - Lotem, Joseph
AU - Polak-Chaklon, Sylvie
AU - Groner, Yoram
N1 - Funding Information:
This work was supported by grants from the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel's Ministry of Science (MOS), the National Institute of Health (USA); the Weizmann Institute's Forchheimer Center of Molecular Genetics; Mr. Bernard Sabrier, Geneva (Switzerland) and the Shapell family biomedical research foundation at the Weizmann Institute.
PY - 1998/9
Y1 - 1998/9
N2 - The human AML1 gene encodes a heterodimeric transcription factor which plays an important role in mammalian hematopoiesis. Several alternatively spliced AML1 mRNA species were identified, some of which encode short protein products that lack the transactivation domain. When transfected into cells these short isoforms dominantly suppress transactivation mediated by the full length AML1 protein. However, their biological function remains obscure. To investigate the role of these short species in cell proliferation and differentiation we generated embryonic stem (ES) cells overexpressing one of the short isoforms, AML1-d, as well as cells expressing the full length isoforms AML1-b and AML2. The in vitro growth rate and differentiation of the transfected ES cells were unchanged. However, overexpression of AML1-d significantly affected the ES cells' ability to form teratocarcinomas in vivo in syngeneic mice, while a similar overexpression of AML1-b and AML2 had no effect on tumor formation. Histological analysis revealed that the AML1-d derived tumors were poorly differentiated and contained numerous apoptotic cells. These data highlight the pleiotropic effects of AML1 gene products and demonstrate for the first time an in vivo growth regulation function for the short isoform AML1-d.
AB - The human AML1 gene encodes a heterodimeric transcription factor which plays an important role in mammalian hematopoiesis. Several alternatively spliced AML1 mRNA species were identified, some of which encode short protein products that lack the transactivation domain. When transfected into cells these short isoforms dominantly suppress transactivation mediated by the full length AML1 protein. However, their biological function remains obscure. To investigate the role of these short species in cell proliferation and differentiation we generated embryonic stem (ES) cells overexpressing one of the short isoforms, AML1-d, as well as cells expressing the full length isoforms AML1-b and AML2. The in vitro growth rate and differentiation of the transfected ES cells were unchanged. However, overexpression of AML1-d significantly affected the ES cells' ability to form teratocarcinomas in vivo in syngeneic mice, while a similar overexpression of AML1-b and AML2 had no effect on tumor formation. Histological analysis revealed that the AML1-d derived tumors were poorly differentiated and contained numerous apoptotic cells. These data highlight the pleiotropic effects of AML1 gene products and demonstrate for the first time an in vivo growth regulation function for the short isoform AML1-d.
KW - AML1 short isoform
KW - Altered in vivo differentiation
KW - ES cells induced teratocarcinomas
KW - Enhanced apoptosis
UR - http://www.scopus.com/inward/record.url?scp=7344248552&partnerID=8YFLogxK
U2 - 10.1038/sj.cdd.4400415
DO - 10.1038/sj.cdd.4400415
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C2 - 10200536
AN - SCOPUS:7344248552
SN - 1350-9047
VL - 5
SP - 765
EP - 773
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 9
ER -