TY - JOUR
T1 - Sleeping beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high-grade astrocytomas
AU - Bender, Aaron M.
AU - Collier, Lara S.
AU - Rodriguez, Fausto J.
AU - Tieu, Christina
AU - Larson, Jon D.
AU - Halder, Chandralekha
AU - Mahlum, Eric
AU - Kollmeyer, Thomas M.
AU - Akagi, Keiko
AU - Sarkar, Gobinda
AU - Largaespada, David A.
AU - Jenkins, Robert B.
PY - 2010/5/1
Y1 - 2010/5/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-09-4674
DO - 10.1158/0008-5472.CAN-09-4674
M3 - Article
C2 - 20388773
AN - SCOPUS:77951702702
SN - 0008-5472
VL - 70
SP - 3557
EP - 3565
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -