Insertional mutagenesis reveals progression genes and checkpoints in MYC/Runx2 lymphomas.
In this study, we have exploited the power of insertional mutagenesis to elucidate tumor progression pathways in mice carrying two oncogenes (MYC/Runx2) that collaborate to drive early lymphoma development. Neonatal infection of these mice with Moloney murine leukemia virus resulted in accelerated tumor onset with associated increases in clonal complexity and lymphoid dissemination. Large-scale analysis of retroviral integration sites in these tumors revealed a profound bias towards a narrow range of target genes, including Jdp2 (Jundm2), D cyclin, and Pim family genes. Remarkably, direct PCR analysis of integration hotspots revealed that every progressing tumor consisted of multiple clones harboring hits at these loci, giving access to large numbers of independent insertion events and uncovering the contrasting mutagenic mechanisms operating at each target gene. Direct PCR analysis showed that high-frequency targeting occurs only in the tumor environment in vivo and is specific for the progression gene set. These results indicate that early lymphomas in MYC/Runx2 mice remain dependent on exogenous growth signals, and that progression can be achieved by constitutive activation of pathways converging on a cell cycle checkpoint that acts as the major rate-limiting step for lymphoma outgrowth.
Stewart
Monica
M
Molecular Oncology Laboratory, Institute of Comparative Medicine, University of Glasgow Veterinary School, Glasgow, Scotland, United Kingdom. m.stewart@vet.gla.ac.uk
Mackay
Nancy
N
Hanlon
Linda
L
Blyth
Karen
K
Scobie
Linda
L
Cameron
Ewan
E
Neil
James C
JC
D000595:Amino Acid Sequence; D000818:Animals; D002472:Cell Transformation, Viral; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D018450:Disease Progression; D018390:Gene Targeting; D016259:Genes, myc; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000235:genetics; D016254:Mutagenesis, Insertional; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D050659:Core Binding Factor Alpha 1 Subunit; C491386:Jundp2 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; C493716:Runx2 protein, mouse; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1