Complementation of non-tumorigenicity of HPV18-positive cervical carcinoma cells involves differential mRNA expression of cellular genes including potential tumor suppressor genes on chromosome 11q13.

The fusion between human tumorigenic cells and normal human diploid fibroblasts results in non-tumorigenic hybrid cells, suggesting a dominant role for tumor suppressor genes in the generated hybrid cells. After long-term cultivation in vitro, tumorigenic segregants may arise. The loss of tumor suppressor genes on chromosome 11q13 has been postulated to be involved in the induction of the tumorigenic phenotype of human papillomavirus (HPV)18-positive cervical carcinoma cells and their derived tumorigenic hybrid cells after subcutaneous injection in immunocompromised mice. The aim of this study was the identification of novel cellular genes that may contribute to the suppression of the tumorigenic phenotype of non-tumorigenic hybrid cells in vivo. We used cDNA microarray technology to identify differentially expressed cellular genes in tumorigenic HPV18-positive hybrid and parental HeLa cells compared to non-tumorigenic HPV18-positive hybrid cells. We detected several as yet unknown cellular genes that play a role in cell differentiation, cell cycle progression, cell-cell communication, metastasis formation, angiogenesis, antigen presentation, and immune response. Apart from the known differentially expressed genes on 11q13 (e.g., phosphofurin acidic cluster sorting protein 1 (PACS1) and FOS ligand 1 (FOSL1 or Fra-1)), we detected novel differentially expressed cellular genes located within the tumor suppressor gene region (e.g., EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) and leucine rich repeat containing 32 (LRRC32) (also known as glycoprotein-A repetitions predominant (GARP)) that may have potential tumor suppressor functions in this model system of non-tumorigenic and tumorigenic HeLa x fibroblast hybrid cells.

MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients.

Between February 1996 and December 2004, the German Leukemia Study Initiative registered 1766 consecutive patients for the acute myeloid leukemia (AML) 96 study, all of whom were diagnosed by central cytomorphology according to the French-American-British (FAB) and the new World Health Organization (WHO) classification. We focused our analysis on the prognostic impact of multilineage dysplasia (MLD) as a new parameter of the WHO classification for AML. We could not confirm the WHO statement that MLD occurs most frequently in older individuals, but we confirmed that MLD is often associated with an unfavorable cytogenetic profile (P < .001). In 1332 individuals receiving intensive AML therapy presence of MLD was negatively correlated with complete remission (P = .001) in univariate, but not in multivariate, analysis. Multivariate analysis of either event-free or overall survival again failed to show an independent prognostic significance of MLD besides age, cytogenetics, and, in part, NPM1/FLT3-ITD mutations. Our data support a reassessment of the WHO classification in the light of a more biologic understanding of AML. This study is registered at www.ClinicalTrials.gov as #NCT00180115.

Association of specific cytogenetic aberrations with mdr1 gene expression in adult myeloid leukemia and its implication in treatment outcome.

BACKGROUND AND OBJECTIVES: Cytogenetics and mdr1 expression are established prognostic factors for treatment outcome in adult acute myeloid leukemia (AML). The association, however, between specific cytogenetic aberrations and mdr1 expression has not yet been examined in a large cohort of patients. DESIGN AND METHODS: We therefore looked for mdr1 gene expression at diagnosis within specific cytogenetic aberrations in 331 previously untreated adult patients with de novo or secondary AML (not including t(15;17)) entered into the German SHG AML96 treatment trial. RESULTS: The proportion of mdr1 positive blast probes was significantly higher in patients with aberrant karyotypes than in those with normal karyotypes (39% vs. 15%; p<0.001). Looking at specific cytogenetic aberrations significantly more mdr1 positive AML patients were found within t(8;21), +8, +21, del(7q), del(5q), -7, abn(3q) and multiple aberrations. In contrast, no patient with inv(16) was positive for mdr1. Only 26% of mdr1 positive patients with aberrant karyotypes achieved complete remission (CR) whereas 54% of the mdr1 negative counterparts did so (p=0.002). Furthermore, within abn(11q), +21, +22, -5 or abn(3q) no mdr1 positive patient reached CR, whereas the mdr1 negative counterparts had CR rates comparable to the CR rate of patients with a normal karyotype. This was most impressive in mdr1 negative patients with multiple aberrations achieving a CR rate of 63% (p=0.019). In the multivariate analysis age, disease status and mdr1 expression were the strongest independent predictors for induction treatment failure. INTERPRETATION AND CONCLUSIONS: The correlation described here between mdr1 gene expression and some cytogenetic aberrations might explain the prognostic divergence of such cytogenetic aberrations in different AML treatment trials due to the amount of mdr-drugs used within the protocols.