Mechanisms Leading to Chromosomal Instability in Oral Cancer Cells

In the United States, cancer is a leading cause of death, second only to heart disease (MOKDAD et al. 2004). Although it is estimated that in 2005, cancer of the oral cavity will account for only 2.1% of cancer cases and 1.3% of overall cancer deaths in the U. S. (JEMAL et al. 2005), high-risk behaviors such as smoking cigarettes, using smokeless tobacco, and consuming excessive alcohol have been shown to play a major role in OSCC development. Exposure to environmental agents, including tobacco products, alcoholic beverages, and/or viruses, such as human papillomavirus (FORASTIERE et al. 2001; HO and CALIFANO 2004; MORK et al. 2001) have a profound influence on cells within the oral cavity. These factors have been shown to induce genetic alterations including chromosomal alterations, DNA changes, and/or epigenetic alterations, such as changes in DNA methylation that affect genetic regulation. Genetic alterations in cells are useful biological markers that assist in early detection of cancer and response to therapy (SIDRANSKY 1995). Currently, however, there are no useful biomarkers to identify early changes involved in OSCC development. One genetic alteration observed in 45% of OSCC is amplification of chromosomal band, 11q13. This event has been shown to follow dysplastic cellular changes, but occur prior to development of carcinoma in situ (FORASTIERE et al. 2001). Therefore, 11q13 amplification may be a useful biomarker for detecting OSCC. In addition, understanding the molecular mechanisms that promote 11q13 gene amplification may provide valuable information for devising novel prevention measures and therapies. In the current study, we show that the primary mechanism promoting 11q13 gene amplification is BFB cycles. Furthermore, we suggest that breakage at the common fragile site, FRA11F, may be responsible for initiating 11q13 gene amplification. By determining the primary mechanism that leads to 11q13 amplification in OSCC, additional investigations focusing on the biological basis of this process may provide important information for developing successful measures and treatments that will increase the survival rate for individuals afflicted with oral cancer

Impaired regeneration in LGMD2A supported by increased Pax7 positive satellite cell content and muscle specific microRNA dysregulation

Introduction—Recent in vitro studies suggest that CAPN3 deficiency leads initially to accelerated myofiber formation followed by depletion of satellite cells (SC). In normal muscle, upregulation of miR-1 and miR-206 facilitates transition from proliferating SCs to differentiating myogenic progenitors. Methods—We examined the histopathological stages, Pax7 SC content, and muscle specific microRNA expression in biopsy specimens from well-characterized LGMD 2A patients to gain insight into disease pathogenesis. Results—Three distinct stages of pathological changes were identified that represented the continuum of the dystrophic process from prominent inflammation with necrosis and regeneration to prominent fibrosis, which correlated with age and disease duration. Pax7-positive SCs were highest in fibrotic group and correlated with down-regulation of miR-1, miR-133a, and miR-206. Conclusions—These observations, and other published reports, are consistent with microRNA dysregulation leading to inability of Pax7-positive SCs to transit from proliferation to differentiation. This results in impaired regeneration and fibrosis.This work was supported by NIH NIAMS U54 AR050733-05, Jesse’s Journey, and the muscular Dystrophy Associatio

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2DBCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrick’s Foundation Scholar Award (to C.G.M.); by a St. Baldrick’s Consortium Award (S.P.H.), by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma Society Special Fellow Award and Alex’s Lemonade Stand Foundation Young Investigator Awards (K.R.), by an Alex’s Lemonade Stand Foundation Award (M.L.) and by National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01 CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171 (The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and C.G.M.); and grants to the COG: U10 CA98543 (Chair’s grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E