Author Block: Mitchell B. Diccianni, George A. Calin, Manuela Ferracin, Chang-gong Liu, Massimo Negrini, Carlos M. Croce, Alice Yu. UCSD, San Diego, CA, Ohio State University, Comprehensive Cancer Center, Columbus, OH, Interdepartment Center for Cancer Research, University of Ferrara, Ferrara, Italy

Abstract Body: MicroRNAs (miRs) are 21-23 nucleotide non-coding RNAs that can positively or negatively regulate target gene expression. miRs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis. We hypothesize that not only will there be miR expression profiles uniquely associated with T-ALL, but miR expression profiles may be predictive of outcome in T-ALL. Total RNA from 43 primary T-ALL samples were assessed by miR chip analysis and compared against the expression profiles of normal mononuclear (MNC) cells. Select samples were validated by quantitative PCR, Northern blot or RNAse protection assay. Results demonstrate that miR expression profiles can clearly differentiate T-ALL from normal MNC and included miR genes that were both expressed at significantly higher levels than normal MNC and at significantly lower levels than normal MNC. Among the up-regulated miR genes, miR-150, located on chromosome 19q13, stands out with relative expression that is more than 10-fold higher than that found in normal MNCs (p<0.0001). Two homologous miR clusters, mir-24-1, mir-23b and mir-27b located on 9q22.1, and mir-24-2, mir-23a and mir-27a located on 19p13.2, were among the miR genes whose expression was most significantly decreased relative to normal MNCs (p= 0.01 - 0.0004). Recent reports in HeLa cells have demonstrated that inhibition of miR-150 expression causes a repression of cell growth while inhibition of miR-24 expression results in growth stimulation. These functions are suggestive that miR-150 may act as an oncogene while mir-24 acts as a tumor suppressor gene, functions that are consistent with our findings of elevated miR-150 and reduced miR-24 expression in T-ALL. Pre-miR expression levels may mirror the expression profile of the mature miR, and in lung cancer pre-miR levels were prognostically significant. Thus, for some miR genes, we have also measured precursor levels. Though significantly decreased at the mature transcript level, miR-24 precursor levels in T-ALL and normal MNC were similar, suggesting that deregulation of this miR was specific to the mature transcript. In summary, our results demonstrate for the first time that miR genes are differentially expressed in T-ALL and identify several miR genes worthy of further exploration for roles in T-ALL pathogenesis. We believe that these analyses will not only yield insights into miR expression profiles unique to T-ALL, but we anticipate that there will be miR expression profiles, either alone or more likely in combination, that can classify T-ALL as to relative risk of failure; these analyses are in progress. 

Additional  References:

1. Avigad S, Hameiri-Grossman M, Cohen IJ, Ash S, Weizman A, and Yaniv I,
"Frequent deletions of specific micro-RNAs in Ewing sarcoma".

2. Esquela-Kerscher A,  and Slack FJ,
"Oncomirs — microRNAs with a role in cancer".

3. Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, and Stoffel M,
"Silencing of microRNAs in vivo with 'antagomirs'".

4. Song X, Sun Y, and Garen A,
"Roles of PSF protein and VL30 RNA in reversible gene regulation".

5. Frenster JH, and Hovsepian JA,
"Ultrastructure of Euchromatin Contact Points between the Closed Loops of Adjacent Interphase Chromosomes".

6. Xu N, Tsai C-L, Lee JT,
"Transient Homologous Chromosome Pairing Marks the Onset of X Inactivation".

RNA and Biological Causality:

A Brief History of Activator RNA.

Links to Euchromatin Activator RNA Reviews:
Links to Euchromatin Activator RNA Research:
Links to Ultrastructural Probes of DNase I-Sensitive Sites:
Links to RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma Immuno-Pathology:
Links to Activated T-Lymphocyte Immunotherapy:
Links to Medical Systems Biology:
Links to Selective Gene Transcription:
Links to RNA-Induced Epigenetics:
Links to RNA-Induced Embryogenesis:
Links to RNA and Biological Causality:
Links to Reprogramming and Neoplasia:

"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".

For Further Information and Feedback:
Phone:  +1 650 367 6483
E-mail: frenster@euchromatin.net