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Uncovering the microRNA landscape in T-cell acute lymphoblastic leukemia

Evelien Mets (UGent)
(2014)
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Uncovering the microRNA landscape in T-cell acute lymphoblastic leukemia
Abstract
T-ALL is an aggressive hematological malignancy that develops in the thymus by uncontrolled proliferation of immature T-cells. T-ALL accounts for 10-15% of pediatric and 25% of adult ALL patients. The current T-ALL treatment protocols consist of multiple chemotherapeutics and lead to a 75% survival rate in children and a 50% survival rate for adults with T-ALL. T-ALL patients can be subdivided in different subgroups, each having genetic lesions that define these subgroups. Additionally, targeted and next generation sequencing led to the discovery of various genetic abnormalities that play part in various cellular processes by targeting important genes in NOTCH1 signaling, cell cycle, hematopoiesis, signal transduction, ribosomal machinery and epigenetic regulation. During the last decade, it has been extensively shown that deregulated miRNA expression contributes to tumorigenesis, but in-depth analysis of miRNAs in the context of T-ALL was not performed yet at the beginning of this thesis. Together with the research group of Prof. Wendel (Memorial Sloan-Kettering Cancer Center, NY, USA), we have demonstrated that known T-ALL tumor suppressor genes are controlled by an extensive network of oncogenic miRNAs, which is presented in the first part of this thesis. We performed miRNA expression profiling on T-ALL patients samples, followed by an independent miRNA library screening finally leading to the identification of five highly expressed miRNAs (miR-19b, miR-20a, miR-26a, miR-92a and miR-223) that are capable of accelerating leukemia onset in a NOTCH1-driven T-ALL mouse model. Furthermore, we also found two less abundantly expressed miRNAs (miR-27a and miR-148a/miR-152) that are able to induce accelerated leukemia onset in this mouse model. All of these miRNAs are part of a cooperative miRNA-tumor suppressive network of important tumor suppressor genes that are involved in T-ALL pathogenesis, namely IKAROS (IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7. In order to further expand the regulatory miRNA network with oncogenes and novel tumor suppressor genes, we performed a miRNAome wide screen of the 3'UTRs of important tumor suppressor genes (PHF6, FBW7, RB1, EZH2) and oncogenes (NOTCH1, MYC and MYB) implicated in T-ALL using a library of 470 miRNA mimic molecules. During the course of this thesis, we decided to focus on the unraveling of the miRNA-MYB and miRNA-PHF6 networks. Integrated analysis of miRNA and mRNA expression data leads to the selection of different miRNAs for further investigation. We selected miR-128-3p and miR-574-3 as top candidate miRNAs targeting PHF6 and miR-193b-3p as top candidate miRNA targeting MYB. Finally in vitro and in vivo modeling capacitated and confirmed the identification of miR-128-3p as a novel tumor suppressor miR, targeting PHF6, and miR-193b-3p as a novel oncomiR, targeting MYB and MCL1 in T-ALL. Future experiments will focus on all the other library screening results, to select other candidate miRNAs. These miRNAs will be assessed similarly as miR-128-3p and miR-193b-3p to further extend the miRNA/mRNA network that is implicated in the development of T-ALL.
Keywords
T-cell acute lymphoblastic leukemia, microRNA

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Citation

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MLA
Mets, Evelien. “Uncovering the microRNA Landscape in T-cell Acute Lymphoblastic Leukemia.” 2014 : n. pag. Print.
APA
Mets, E. (2014). Uncovering the microRNA landscape in T-cell acute lymphoblastic leukemia. Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium.
Chicago author-date
Mets, Evelien. 2014. “Uncovering the microRNA Landscape in T-cell Acute Lymphoblastic Leukemia”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
Chicago author-date (all authors)
Mets, Evelien. 2014. “Uncovering the microRNA Landscape in T-cell Acute Lymphoblastic Leukemia”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
Vancouver
1.
Mets E. Uncovering the microRNA landscape in T-cell acute lymphoblastic leukemia. [Ghent, Belgium]: Ghent University. Faculty of Medicine and Health Sciences; 2014.
IEEE
[1]
E. Mets, “Uncovering the microRNA landscape in T-cell acute lymphoblastic leukemia,” Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium, 2014.
@phdthesis{5774117,
  abstract     = {T-ALL is an aggressive hematological malignancy that develops in the thymus by uncontrolled proliferation of immature T-cells. T-ALL accounts for 10-15% of pediatric and 25% of adult ALL patients. The current T-ALL treatment protocols consist of multiple chemotherapeutics and lead to a 75% survival rate in children and a 50% survival rate for adults with T-ALL. T-ALL patients can be subdivided in different subgroups, each having genetic lesions that define these subgroups. Additionally, targeted and next generation sequencing led to the discovery of various genetic abnormalities that play part in various cellular processes by targeting important genes in NOTCH1 signaling, cell cycle, hematopoiesis, signal transduction, ribosomal machinery and epigenetic regulation. During the last decade, it has been extensively shown that deregulated miRNA expression contributes to tumorigenesis, but in-depth analysis of miRNAs in the context of T-ALL was not performed yet at the beginning of this thesis.
Together with the research group of Prof. Wendel (Memorial Sloan-Kettering Cancer Center, NY, USA), we have demonstrated that known T-ALL tumor suppressor genes are controlled by an extensive network of oncogenic miRNAs, which is presented in the first part of this thesis. We performed miRNA expression profiling on T-ALL patients samples, followed by an independent miRNA library screening finally leading to the identification of five highly expressed miRNAs (miR-19b, miR-20a, miR-26a, miR-92a and miR-223) that are capable of accelerating leukemia onset in a NOTCH1-driven T-ALL mouse model. Furthermore, we also found two less abundantly expressed miRNAs (miR-27a and miR-148a/miR-152) that are able to induce accelerated leukemia onset in this mouse model. All of these miRNAs are part of a cooperative miRNA-tumor suppressive network of important tumor suppressor genes that are involved in T-ALL pathogenesis, namely IKAROS (IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7.
In order to further expand the regulatory miRNA network with oncogenes and novel tumor suppressor genes, we performed a miRNAome wide screen of the 3'UTRs of important tumor suppressor genes (PHF6, FBW7, RB1, EZH2) and oncogenes (NOTCH1, MYC and MYB) implicated in T-ALL using a library of 470 miRNA mimic molecules. During the course of this thesis, we decided to focus on the unraveling of the miRNA-MYB and miRNA-PHF6 networks. Integrated analysis of miRNA and mRNA expression data leads to the selection of different miRNAs for further investigation. We selected miR-128-3p and miR-574-3 as top candidate miRNAs targeting PHF6 and miR-193b-3p as top candidate miRNA targeting MYB. Finally in vitro and in vivo modeling capacitated and confirmed the identification of miR-128-3p as a novel tumor suppressor miR, targeting PHF6, and miR-193b-3p as a novel oncomiR, targeting MYB and MCL1 in T-ALL.
Future experiments will focus on all the other library screening results, to select other candidate miRNAs. These miRNAs will be assessed similarly as miR-128-3p and miR-193b-3p to further extend the miRNA/mRNA network that is implicated in the development of T-ALL.},
  author       = {Mets, Evelien},
  keywords     = {T-cell acute lymphoblastic leukemia,microRNA},
  language     = {eng},
  pages        = {X, 193},
  publisher    = {Ghent University. Faculty of Medicine and Health Sciences},
  school       = {Ghent University},
  title        = {Uncovering the microRNA landscape in T-cell acute lymphoblastic leukemia},
  year         = {2014},
}