Expression of c-MYC under the control of GATA-1 regulatory sequences causes erythroleukemia in transgenic mice.
To study oncogenesis in the erythroid lineage, we have generated transgenic mice carrying the human c-MYC proto-oncogene under the control of mouse GATA-1 regulatory sequences. Six transgenic lines expressed the transgene and displayed a clear oncogenic phenotype. Of these, five developed an early onset, rapidly progressive erythroleukemia that resulted in death of the founder animals 30-50 d after birth. Transgenic progeny of the sixth founder, while also expressing the transgene, remained asymptomatic for more than 8 mo, whereupon members of this line began to develop late onset erythroleukemia. The primary leukemic cells were transplantable into nude mice and syngeneic hosts. Cell lines were established from five of the six leukemic animals and these lines, designated erythroleukemia/c-MYC (EMY), displayed proerythroblast morphology and expressed markers characteristic of the erythroid lineage, including the erythropoietin receptor and beta-globin. Moreover, they also manifested a limited potential to differentiate in response to erythropoietin. Studies in the surviving transgenic line indicated that, contrary to our expectations, the transgene was not expressed in the mast cell lineage. That, coupled with the exclusive occurrence of erythroleukemia in all the transgenic lines, suggests that the GATA-1 promoter construct we have used includes regulatory sequences necessary for in vivo erythroid expression only. Additional sequences would appear to be required for expression in mast cells. Further, our results show that c-MYC can efficiently transform erythroid precursors if expressed at a vulnerable stage of their development.
Skoda
R C
RC
Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Tsai
S F
SF
Orkin
S H
SH
Leder
P
P
D000818:Animals; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics*; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation; D016259:Genes, myc; D004915:Leukemia, Erythroblastic, Acute / Q000209:etiology / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors