Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. C3PO, component 3 promoter of RISC TRBP, TAR RNA binding protein.Ībdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL. The miRNA-RISC (miRISC) is then capable of targeting mRNA transcripts for repression through a variety of mechanisms ( right bottom). DICER further cleaves the pre-miRNA to a miRNA duplex and selects the miRNA with the least stable 5′-end for loading into the RNA-induced silencing complex (RISC), whose primary constituent is an Argonaute (Ago) protein ( right top). Pre-miRNAs are exported from the nucleus by EXPORTIN-5 and they meet DICER in the cytoplasm. miRNAs generated from introns and miRtrons bypass DROSHA cleavage and proceed as pre-miRNAs and normal processing ( left bottom). For miRNAs that are not derived from an intron, i.e., miRNAs encoded in their own genes ( left top), in polycistrons, or in the nonprotein-coding regions of host genes ( left middle), hairpin primary-miRNAs (pri-miRNAs) are recognized by DROSHA, which utilizes RNAse III activity to trim the pri-miRNAs to precursor miRNAs (pre-miRNAs). miRNA biogenesis begins in the nucleus, where miRNA-encoding genes are transcribed. Finally, we will discuss the promise of MiRNA-based therapeutics and challenges for the future study of disease-causing MiRNAs.Ĭancer Hematopoiesis Leukemia MiRNA MiRNA therapeutics MicroRNA. So, with a special focus on the hematologic system, we will discuss how MiRNAs contribute to differentiation of stem cells and how dysregulation of MiRNAs contributes to the development of malignancy, by providing examples of specific MiRNAs that function as oncogenes or tumor suppressors, as well as of defects in MiRNA processing. Strikingly, many of the studies that have expanded our understanding of the contributions of MiRNAs to normal physiology and in the development of diseases have come from studies in the hematopoietic system and hematologic malignancies, with some of the earliest identified functions for mammalian MiRNAs coming from observations made in leukemias. In this review, we explore the discovery of MiRNAs, their mechanism of action, and the tools that aid in their discovery and study. Given their importance, it is predictable that dysregulation of MiRNAs, which target a wide variety of transcripts, can result in malignant transformation. MicroRNAs (MiRNAs) are a class of endogenously encoded ~22 nucleotide, noncoding, single-stranded RNAs that contribute to development, body planning, stem cell differentiation, and tissue identity through posttranscriptional regulation and degradation of transcripts.
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