Oncogenic miR-9 targets RYBP in MLL-rearranged AML /

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Bibliographic Details
Author / Creator:Price, Colles Orrin Joseph, author.
Ann Arbor : ProQuest Dissertations & Theses, 2015
Description:1 electronic resource (180 pages)
Format: E-Resource Dissertations
Local Note:School code: 0330
URL for this record:http://pi.lib.uchicago.edu/1001/cat/bib/10773330
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Other authors / contributors:University of Chicago. degree granting institution.
Notes:Advisors: Jianjun Chen; Janet Rowley Committee members: Lucy Godley; Geoffrey Greene; Michelle Le Beau.
Dissertation Abstracts International, Volume: 77-02(E), Section: B.
Summary:Acute Myeloid Leukemia (AML) is a disease of the bone marrow that continues to be a problem in human health despite advances in cancer therapy. This disease is characterized by the uncontrolled clonal expansion of hematopoietic immature progenitors with a block in differentiation. Furthermore,AML has multiple subtypes which include those with chromosomal rearrangements. Within those subtypes, chromosomal rearrangements involving the mixed lineage leukemia (MLL) gene are marked with a poor to intermediate survival. MLL protein is a chromatin modifier and known to be a transcriptional activator in normal and malignant cells and rearrangements involving MLL are sufficient to induce leukemia. Although MLL's effect on chromatin and histone modifications and how that leads to gene transcription has been well understood, its effect on the regulation of noncoding RNAs remains elusive.
An emerging hallmark in cancer is that microRNAs (miRNAs), an abundant class of short nucleotides of noncoding RNAs, are deregulated in the pathogenesis of cancer. Those miRNAs serve as regulators of transcription by binding to the complementary mRNA sequences at the 3'untranslated region (UTR), leading to a block in translation or inducing mRNA degradation. Those miRNAs can serve either as oncogenes or tumor suppressors and a single miRNA can potentially regulate hundreds of genes.
Using both internally generated miRNA-expression arrays in AML patients and publically available RNA-sequencing and miRNA-sequencing data from the Cancer Genome Atlas (TCGA) I have identified that microRNA-9 (miR-9) is upregulated specifically in MLL-rearranged AML in patient samples, human cell lines and transformed murine hematopoietic cells. I found miR-9 itself is epigenetically activated by both MLL-rearrangements and by wildtype MLL.
. Furthermore, overexpression of miR-9 significantly increases leukemic growth, blocks differentiation and reduces apoptosis in vitro and in vivo. I identified a novel miR-9 target, RYBP (Ring1- and YY1- Binding Protein), is downregulated in leukemogenesis. Forced expression of RYBP significantly attenuates MLL-rearrangedAML in vitro and in vivo and is shown to be a tumor suppressor. Furthermore, expression of RYBP induces apoptosis in transplanted leukemic cells and induces differentiation, showing it is a key regulator in MLL -rearranged pathogenesis. Genomic analysis of miR-9 overexpression shows critical regulation of oncogenic pathways including activation of pro-metabolic pathways and inhibition of anti-differentiation pathways while genomic analysis of RYBP expression shows inhibition of several oncogenic kinases and targets of the Polycomb complex. Together, these results identify a novel leukemic pathway within MLL-rearrangedAML that was previously unknown and suggests a new mechanism underlying leukemogenesis and leukemia progression.