Page 72 - Hematology_ Basic Principles and Practice ( PDFDrive )

44 Part I Molecular and Cellular Basis of Hematology

how they regulate gene expression. For example, the specificity of mRNA transcripts for stability, (4) packaging the mRNA for export
miRNA targeting is ruled by Watson–Crick complementarities from the nucleus to the cytoplasm, and (5) regulation by miRNA.
between positions 2 and 8 at the 5′ end of the miRNA and the 3′ The ultimate goal of most posttranscriptional modifications is to
UTR of their target mRNAs. make the mRNA available for translation into proteins. Perturbations
Two models have been proposed to explain how miRNAs and in any of these steps can result in hematologic disease. However, while
siRNAs interfere with the expression of target genes. These models the regulation of RNA has risk of disease at every step, it also possesses
are: directed degradation of the target mRNA, or interference with the promise of therapeutic intervention. Indeed, RNA metabolism
the translation of a target mRNA. In the case of directed mRNA has been an under-explored pathway for drug development in hema-
degradation, the proposed model involves miRNA–mRNA binding tology, but that deficit is rapidly being overcome as more attention
and recruitment of RISC, which ultimately leads to degradation of is being paid to targeting aberrant RNA pathways in an effort to
the target mRNA. In the interference model it is believed that the restore normal gene expression.
interaction of miRNA, RISC, and mRNA blocks the ribosomal
machinery along the mRNA transcript, preventing translation yet
sparing the mRNA from degradation. This latter model was hypoth- SUGGESTED READINGS
esized based on work on the Caenorhabditis elegans gene lin-14. In
this example the amount of lin-14 mRNA does not decrease, but the Garzon R, Marucci G, Croce C: Targeting microRNAs in cancer: rationale,
protein product of the lin-14 mRNA is reduced. In the degradation strategies and challenges. Nat Rev Drug Discov 9:775–789, 2010.
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stranded ribonucleases, which are thought to be part of the innate trans-splicing and DNA repair: a vicious path to cancer. Am J Blood Res
immune system as a defense against dsRNA viruses, like rotavirus. 1:1–12, 2011.
Various disease states have aberrant expression of miRNA. One Li B, Carey M, Workman J: The role of chromatin during transcription. Cell
example in chronic lymphocytic leukemia (CLL) is the miR-15a/ 128:707–719, 2007.
miR16-1 cluster (located on chromosome 13q). When this cluster is Rice K, Hormaeche I, Licht J: Epigeneic regulation of normal and malignant
deleted in B lymphocytes, there are higher levels of antiapoptotic hematopoiesis. Oncogene 26:6697–6714, 2007.
proteins such as BCL2 and MCL1, but also higher levels of the tumor Schwartz S, Ast G: Chromatin density and splicing destiny: on the cross-talk
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tions in CLL are associated with an indolent form of the disease. 3:13–25, 2012.
Patterns of miRNA expression are correlated with disease progression Valencia-Sanchez M, Liu J, Hannon G, et al: Control of translation and
in CML, although it is not clear whether these changes are causative mRNA degradation by miRNAs and siRNAs. Genes Dev 20:515–524,
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expression levels fall significantly when CML begins to progress to ceosomal machinery in myelodysplastic syndromes and other hematologic
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with several steps including: (1) DNA transcription into RNA, (2) tination. Genes Dev 17:2733–2740, 2003.
splicing of mRNA into translatable transcripts, (3) modifying the