Large-Scale Mutagenesis in p19ARF- and p53-Deficient Mice Identifies Cancer Genes and Their Collaborative Networks

Abstract

Summaryp53 and p19ARF are tumor suppressors frequently mutated in human tumors. In a high-throughput screen in mice for mutations collaborating with either p53 or p19ARF deficiency, we identified 10,806 retroviral insertion sites, implicating over 300 loci in tumorigenesis. This dataset reveals 20 genes that are specifically mutated in either p19ARF-deficient, p53-deficient or wild-type mice (including Flt3, mmu-mir-106a-363, Smg6, and Ccnd3), as well as networks of significant collaborative and mutually exclusive interactions between cancer genes. Furthermore, we found candidate tumor suppressor genes, as well as distinct clusters of insertions within genes like Flt3 and Notch1 that induce mutants with different spectra of genetic interactions. Cross species comparative analysis with aCGH data of human cancer cell lines revealed known and candidate oncogenes (Mmp13, Slamf6, and Rreb1) and tumor suppressors (Wwox and Arfrp2). This dataset should prove to be a rich resource for the study of genetic interactions that underlie tumorigenesis.

It's T-ALL about Notch

“…These data indicate that loss of Ik tumor suppressor function is a cooperative event with Notch activation in leukemogenesis. Furthermore, a recent report from the Berns group confirms that mutation in Notch and Ik is concomitant in a high percentage of MuLV-derived T-cell tumors in mice (Uren et al, 2008).…”

“…As Notch suppresses p53, this would indicate that activating mutations in the Notch pathway and loss of p53 activity would be mutually exclusive events. Indeed, in a comparison of lymphomas generated by MuLV insertional mutagenesis of p53 wild type and p53 À/À mice, Notch insertions were primarily found in p53 wild-type compared to p53 À/À tumors (Uren et al, 2008).…”

RREB1 Transcription Factor Splice Variants in Urologic Cancer

“…23 Furthermore, RREB1 was identified as a potential oncogene in Moloney murine leukemia virus (MuLV) infected p19 ARF and p53 knockout mice. 24 Finally, the human RREB1 locus has been found to be amplified in melanoma and is currently an area of intense investigation for its potential in molecular diagnostic testing. [25][26][27][28][29][30] In prostate cancer, RREB1 binds the PSA promoter only in association with AR to repress transcription.…”

Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL

“…Mice with germline mutations that inactivate the transcriptional regulator Ikaros (gene symbol Ikzf1) develop T-ALL exclusively [23,25] and the resulting malignancies often have activating NOTCH1 mutations [6,23,24]. Ikzf1 somatic mutations are also frequently found in combination with NOTCH1 mutations in mouse retrovirus-promoted T-ALL [18] and in human B-ALL and T-ALL [26,27]. Short, dominant negative forms of Ikaros generated by alternative splicing have also been found in human T-ALL [28,29] although this has not been found in other T-ALL series [30].…”

“…The ICN then translocates into the nucleus and associates with the transcription factor CSL or RBP-J and Mastermind-like 1-3 [17]. This complex activates transcription of Notch target genes including Myc, PTEN/PI3K, NFkB, Hes1, PreT˛ [18]. Not only mutations in NOTCH1 itself can lead to leukemogenesis, cooperating mutations in Notch target genes [19] and regulators (e.g.…”