Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein-coding genes - PubMed (original) (raw)

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Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein-coding genes

George A Calin et al. Blood. 2009.

Abstract

One of the most unexpected and fascinating discoveries in oncology over the past few years is the interplay between abnormalities in protein-coding genes and noncoding RNAs (ncRNAs) that is causally involved in cancer initiation, progression, and dissemination. MicroRNAs (miRNAs), small regulatory ncRNAs, are involved in the pathogenesis of all types of human cancers, including leukemias, mainly via dysregulation of expression of cancer genes. Increasing evidence shows that miRNAs can work as tumor suppressors (inhibiting malignant potential) or oncogenes (activating malignant potential). Researchers first identified this new paradigm of molecular oncology in patients with chronic lymphocytic leukemia (CLL). Understanding the roles of miRNAs and other ncRNAs in leukemic cells is not only uncovering a new layer of gene regulation but also providing new markers for improved diagnosis and prognosis, as well as novel therapeutic options for CLL patients. Herein we focus on the roles of miRNAs and ultraconserved ncRNA genes in CLL, highlighting what is already known about their function, proposing a novel model of CLL predisposition and progression, and describing the challenges for the near future.

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Figures

Figure 1

Figure 1

**Involvement of ncRNAs in human leukemias.**miRNAs regulate the expression of protein-coding genes and can act as oncogenes, tumor suppressors, or both. UCGs, which are regulated by miRNAs, can act as oncogenes, whereas their role as tumor suppressors has been hypothesized but has not been experimentally proven until now. The main examples of protein coding targeted by miRNAs are presented.

Figure 2

Figure 2

MiRNA involvement in CLL predisposition. MiRNA alterations can predispose people to CLL development. This proposed model shows structural and/or expression abnormalities of miRNAs in the germline that may represent inherited predisposing events. For simplicity, only gene deletion is shown, but all other types of loss-of-function and gain-of-function mutations described for PCGs can be involved in miRNA disruption (blue color). For CLL to develop, a second genetic event in addition to the predisposing one must occur in a somatic cell (green color). This can be a PCG alteration or a “hit” in another miRNA (presented here as amplification of expression). The consequences of these abnormalities are reflected by the levels of expression of various target mRNAs: overexpression of target oncogenes in the case of miRNA deletion and down-regulation of expression of target TSGs in the case of miRNA amplification.

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