Long non-coding RNAs in haematological malignancies

Abstract

Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. LncRNAs are as diverse as mRNAs and they normally share the same biosynthetic machinery based on RNA polymerase II, splicing and polyadenylation. However, lncRNAs have low coding potential. Compared to mRNAs, lncRNAs are preferentially nuclear, more tissue specific and expressed at lower levels. Most of the lncRNAs described to date modulate the expression of specific genes by guiding chromatin remodelling factors; inducing chromosomal loopings; affecting transcription, splicing, translation or mRNA stability; or serving as scaffolds for the organization of cellular structures. They can function in cis, cotranscriptionally, or in trans, acting as decoys, scaffolds or guides. These functions seem essential to allow cell differentiation and growth. In fact, many lncRNAs have been shown to exert oncogenic or tumor suppressor properties in several cancers including haematological malignancies. In this review, we summarize what is known about lncRNAs, the mechanisms for their regulation in cancer and their role in leukemogenesis, lymphomagenesis and hematopoiesis. Furthermore, we discuss the potential of lncRNAs in diagnosis, prognosis and therapy in cancer, with special attention to haematological malignancies.

Figure 1

Schematic representation of cis and trans-acting lncRNAs. cis-acting lncRNAs function at the site of transcription and affect the expression of neighbouring genes. Trans-acting lncRNAs function away from the site of synthesis.

Figure 2

Schematic representation of the function of lncRNAs deregulated in haematological malignancies. (A) BIC. Myb transcription factor increases the expression of BIC in several leukemias and lymphomas. This results in increased levels of miR-155 and miR-155-mediated downregulation of several tumor suppressor genes; (B) ANRIL. The INK4 p15INK4b-p14ARF-p16INK4a cluster transcribes for an antisense transcript named ANRIL; PcG complex (PRC2) is targeted to the INK4 locus by ANRIL, and locus expression is inhibited; (C) MEG3. MEG3, among other functions, stimulates p53-dependent tumor suppressor pathways by several mechanisms. MEG3 down-regulates MDM2 expression, therefore decreasing p53 MDM2-mediated degradation. MEG3 increases p53 protein levels and stimulates p53-dependent transcription. MEG3 enhances p53 binding to some target promoters such as GDF15; (D) GAS5. GAS5 binds the DNA binding domain of glucocorticoid receptors (GR) and impedes GR binding to DNA and induction of GR-dependent genes such as cIAP2.