The Runx genes: lineage-specific oncogenes and tumor suppressors

Abstract

The Runx genes present a challenge to the simple binary classification of cancer genes as oncogenes or tumor suppressors. There is evidence that loss of function of two of the three mammalian Runx genes promotes cancer, but in a highly lineage-restricted manner. In human leukemias, the RUNX1 gene is involved in various chromosomal translocation events that create oncogenic fusion proteins, at least some of which appear to function as dominant-negative inhibitors of the normal gene product. Paradoxically, evidence is mounting that structurally intact Runx genes are also oncogenic when overexpressed. All the three murine genes act as targets for transcriptional activation by retroviral insertional mutagenesis, and the oncogenic potential of Runx2 has been confirmed in transgenic mice. Moreover, the RUNX1 gene is often amplified or overexpressed in cases of acute leukemia. The state of progress in elucidating the oncogenic roles of the Runx genes is the subject of this review, and we draw together recent observations in a tentative model for the effects of Runx deregulation on hematopoietic cell differentiation. We suggest that lineage-specific factors determine the sensitivity to the oncogenic effects of loss or overexpression of Runx factors.

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

“…TEL-AML1 retains virtually the full-length AML1 gene product and it has been suggested that this fusion may be functionally analogous to overexpression of normal AML1 (Cameron and Neil, 2004). However, this does not appear to be the explanation for the effects of TEL-AML1 on in vitro B-cell development in our experiments, as AML1 overexpression inhibited B-cell growth and differentiation.…”

“…All constructs were tagged with an HA epitope as indicated. Overexpression of AML1 inhibits B-cell development in vitro As the TEL-AML1 fusion protein retains virtually the entire AML1 protein, it has been suggested that some of the effects of TEL-AML1 on hematopoiesis may simply be the result of deregulated AML1 expression (Cameron and Neil, 2004). In order to determine whether the TEL moiety of the fusion is required to promote B-cell differentiation in vitro, we included a construct expressing full length AML1 in the experiments above.…”

RUNX3 protein is overexpressed in human basal cell carcinomas

“…Moreover, RUNX3 is also a downstream target of the TGF-b tumor suppressor pathway. Although all members of the RUNX family, most notably RUNX2, are known to promote tumorigenecity in mouse models (Cameron and Neil, 2004;Yanagida et al, 2005), our study implicates RUNX3 acting as a putative oncogene in human cancer.…”

Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas

“…Overexpression of XBP1 suggests that this transcription factor could play a role in the development of B-cell hyperplasia in AIL lesions, since it is known to be a crucial factor influencing B-cell and plasma cell differentiation (Chauhan et al, 2003;Munshi et al, 2004;Shaffer et al, 2004). RUNX1 may also be related to AIL pathogenesis, since it is known to be often overexpressed in acute leukemia (Cameron and Neil, 2004).…”