The mammalian genome contains several hundred microRNAs that regulate gene expression through modulation of target mRNAs. Here, we report a fragile chromosomal region lost in specific hematopoietic malignancies. This 7 Mb region encodes about 12% of all genomic microRNAs, including miR-203. This microRNA is additionally hypermethylated in several hematopoietic tumors, including chronic myelogenous leukemias and some acute lymphoblastic leukemias. A putative miR-203 target, ABL1, is specifically activated in these hematopoietic malignancies in some cases as a BCR-ABL1 fusion protein (Philadelphia chromosome). Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1-dependent manner. Thus, miR-203 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in specific hematopoietic malignancies.

A wide panel of murine induced T-cell lymphomas have been analysed for p16 INK4a or p15 INK4b alterations. Only one g-radiation-induced lymphoma showed p16 INK4a homozygous deletion and no other intragenic mutations were found in these INK4 genes. However, de novo methylation of the 5' CpG islands of the murine p15 INK4b and p16 INK4a genes was found to be highly frequent. While p16 INK4a hypermethylation was found in 36% of the neutron-radiation-induced lymphomas and 15% of the gradiation-induced lymphomas, de novo methylation of p15 INK4b occurs in 88% and 42% of these tumors respectively, correlating with de®cient expression of the corresponding mRNA and allelic losses in the p15 INK4b and p16 INK4a chromosome location. These data represent, to our knowledge, the ®rst report on the signi®cant involvement of hypermethylation of these INK4 genes in murine primary tumors. Moreover, they show the importance of allelic losses and CpG island methylation of p15 INK4b gene inactivation and support a tumor suppressor role for p15 INK4b in T-cell lymphomas independent of p16 INK4a .

Endoglin is a membrane glycoprotein that acts as a coreceptor for transforming growth factor-B. We and others have previously suggested a function of endoglin as a tumor suppressor in epithelial cancer. Here, we study the expression of endoglin during chemical mouse skin carcinogenesis. We find that shedding of membrane endoglin, allowing the secretion of a soluble endoglin form, is a late event associated with progression from squamous to spindle cell carcinomas. Knockdown of endoglin in transformed keratinocytes activates the Smad2/3 signaling pathway resulting in cell growth arrest, delayed tumor latencies, and a squamous to spindle phenotypic conversion. Forced expression of the long endoglin isoform in spindle carcinoma cells blocks transforming growth factor-B1 stimulation of Smad2/3 signaling and prevents tumor formation. In contrast, expression of the short endoglin isoform has no effect on spindle cell growth in vitro or in vivo. Our results show that endoglin behaves as a suppressor of malignancy during the late stages of carcinogenesis. Therefore, disruption of membrane endoglin emerges as a crucial event for progression to spindle cell carcinomas. [Cancer Res 2007;67(21):10268-77]