Sleeping beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high-grade astrocytomas.
The Sleeping Beauty (SB) transposon system has been used as an insertional mutagenesis tool to identify novel cancer genes. To identify glioma-associated genes, we evaluated tumor formation in the brain tissue from 117 transgenic mice that had undergone constitutive SB-mediated transposition. Upon analysis, 21 samples (18%) contained neoplastic tissue with features of high-grade astrocytomas. These tumors expressed glial markers and were histologically similar to human glioma. Genomic DNA from SB-induced astrocytoma tissue was extracted and transposon insertion sites were identified. Insertions in the growth factor gene Csf1 were found in 13 of the 21 tumors (62%), clustered in introns 5 and 8. Using reverse transcription-PCR, we documented increased Csf1 RNAs in tumor versus adjacent normal tissue, with the identification of transposon-terminated Csf1 mRNAs in astrocytomas with SB insertions in intron 8. Analysis of human glioblastomas revealed increased levels of Csf1 RNA and protein. Together, these results indicate that SB-insertional mutagenesis can identify high-grade astrocytoma-associated genes and they imply an important role for CSF1 in the development of these tumors.
Bender
Aaron M
AM
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Collier
Lara S
LS
Rodriguez
Fausto J
FJ
Tieu
Christina
C
Larson
Jon D
JD
Halder
Chandralekha
C
Mahlum
Eric
E
Kollmeyer
Thomas M
TM
Akagi
Keiko
K
Sarkar
Gobinda
G
Largaespada
David A
DA
Jenkins
Robert B
RB
D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004251:DNA Transposable Elements; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000379:methods*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D019895:Transposases / Q000235:genetics*
D004251:DNA Transposable Elements; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019895:Transposases
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