Functional validation of genes implicated in lymphomagenesis: an in vivo selection assay using a Myc-induced B-cell tumor.
The involvement of the c-Myc transcription factor in neoplastic transformation is well documented. However, which of its numerous target genes are crucial for tumorigenesis remains a frequently contested issue. We have recently established a non-transgenic murine model for B-cell lymphoma based on neoplastic conversion of p53-null bone marrow cells by conditionally active Myc. Using this model, we have identified a number of genes whose expression levels are affected by Myc during B-lymphomagenesis. Here we discuss their possible roles in neoplastic processes and describe an experimental approach allowing in vivo validation of these roles. We demonstrate that lymphoma cells overexpressing one of the Myc targets, the interleukin-10 receptor gene, have a very strong selective advantage over low IL10R expressors. Furthermore, Mcl1, a presumptive IL10R effector, also confers selective advantages when overexpressed in Myc-transformed hematopoietic cells. Thus, both IL10R and Mcl1 might be amenable to therapeutic interventions, and new targets can be identified and validated using the selection approach.
Yu
Duonan
D
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104-6051, USA.
Cozma
Diana
D
Park
Andrea
A
Thomas-Tikhonenko
Andrei
A
D000818:Animals; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D053701:Receptors, Interleukin-10; D012190:Retroviridae / Q000378:metabolism
C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10