Expression of AML1-d, a short human AML1 isoform, in embryonic stem cells suppresses in vivo tumor growth and differentiation.
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.
Aziz-Aloya
R B
RB
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, 76100 Israel.
Levanon
D
D
Karn
H
H
Kidron
D
D
Goldenberg
D
D
Lotem
J
J
Polak-Chaklon
S
S
Groner
Y
Y
D000818:Animals; D015197:Carcinogenicity Tests; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D051379:Mice; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection
D050676:Core Binding Factor Alpha 2 Subunit; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta; C493726:Runx1 protein, mouse; D014157:Transcription Factors