Misexpression of disrupted HMGI architectural factors activates alternative pathways of tumorigenesis.

Abstract

Cancer arises from aberrations in the genetic mechanisms that control growth and differentiation. HMGI-C and HMGI(Y) are members of the HMGI family of architectural factors expressed in embryonic or undifferentiated cells and highly associated with transformation. Translocations of 12q13-15 in lipomas (fat cell tumors) disrupt HMGI-C and fuse its DNA-binding domains to novel transcriptional regulatory domains. This study shows that in a rare, karyotypically distinct group of human lipomas, rearrangements of 6p21-23 produce internal deletions within HMGI(Y). Activation of the rearranged alleles leads to expression of aberrant HMGI(Y) transcripts in differentiated adipocytes. A molecular analysis of these transcripts demonstrates that fusion of HMGI DNA-binding domains to putative transcriptional regulatory domains was not necessary for lipoma formation. However, such fusions may facilitate tumor development because activation of the wild-type HMGI allele, normally required for tumorigenesis, is bypassed in lipomas which express chimeric HMGI proteins. We hypothesize that HMGI misexpression in a differentiated cell is a pivotal event in benign tumorigenesis, and the molecular pathway of tumor development depends upon the precise nature of HMGI disruption.