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Role of Microrna-29 in the Pathogenesis of B-Cell Chronic Lymphocytic Leukemia

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Role of Microrna-29 in the Pathogenesis of B-Cell Chronic Lymphocytic Leukemia Role of microRNA-29 in the Pathogenesis of B-Cell Chronic Lymphocytic Leukemia DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Urmila Santanam Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2010 Dissertation Committee: Dr. Carlo M. Croce, Advisor Dr. Kay Huebner Dr. Denis Guttridge Dr. Amanda Toland Copyright by Urmila Santanam 2010 Abstract B-cell chronic lymphocytic leukemia (B-CLL), the most common human leukemia in the world, is a malignancy of mature B-lymphocytes. Deregulation of the TCL1 oncogene is a causal event in the pathogenesis of the aggressive form of this disease as was verified by using animal models. To study the mechanism of TCL1 regulation in CLL, we carried out microRNA expression profiling of three types of CLL: indolent CLL, aggressive CLL, and aggressive CLL showing 11q deletion. We identified distinct microRNA signatures corresponding to each group of CLL. We further determined that TCL1 expression is regulated by miR-29 and miR-181, two microRNAs differentially expressed in CLL. Expression levels of miR-29 and miR-181 generally inversely correlated with TCL1 expression in the CLL samples we examined. Our results suggest that TCL1 expression in CLL is, at least in part, regulated by miR-29 and miR- 181 and that these microRNAs may be candidates for therapeutic agents in CLLs overexpressing TCL1. Human B-CLL occurs in two forms: aggressive (showing high ZAP-70 expression and unmutated IgH VH) and indolent (showing low ZAP-70 expression and mutated IgH VH). We found that miR-29a is upregulated in indolent human B-CLL compared to aggressive B-CLL and normal CD19+ B-cells. To study the role of miR- 29 in B-CLL, we generated Eµ-miR-29 transgenic mice overexpressing miR-29 in mouse B-cells. Flow cytometric analysis revealed a markedly expanded CD5+ population in the ii spleen of these mice starting at 2 months of age. 85% (34/40) of miR-29 transgenic mice exhibited an expanded population of CD5+ B-cells, a characteristic of the B-CLL phenotype. An average of 50% of the B-cell population in these transgenics was CD5 positive. At the age of 2 years these mice showed significantly enlarged spleens and an increase in CD5+ B-cell population of up to 100% of B-cells. Of 20 Eµ-miR-29 transgenic mice followed up to the age of 24-26 months, 4 (20%) developed frank leukemia and prematurely died from the disease. The expanded CD5+ B-cell population was found to be proliferative, with an increased number of cells in the S-phase of the cell cycle, compared to wild type CD19+ B-cells. These results suggest that deregulation of miR-29 can cause, or at least significantly contribute to the pathogenesis of indolent B- CLL. Although many microRNAs are up- or down-regulated in a number of solid tumors and hematological malignancies and several are postulated to function as tumor suppressors or oncogenes, there have been only two reports demonstrating that up- regulation of a single microRNA can cause malignancy. Here we demonstrate that up- regulation of miR-29 in human indolent CLL is an important initiating event in the pathogenesis of this disease. These results show that overexpression of miR-29 is sufficient to cause the development of indolent CLL with high penetrance and provide a new mouse model for indolent CLL. iii Dedication This document is dedicated to my parents. iv Acknowledgments First, I would like to thank my advisor Dr Carlo Croce for having me as a student in his lab and for his continuous support and encouragement. I thank Dr. Yuri Pekarsky for guiding me through my work, and for his valuable counsel. I would like to thank my committee members, Dr. Kay Huebner, Dr. Denis Guttridge and Dr. Amanda Toland, for their time and guidance. I am grateful to my program director, Dr. David Bisaro, and the MCDB program co-ordinator Jan Zinaich. I also thank our lab administrative staff, Sharon Palko, Dorothee Wernicke-Jameson, Susan Lutz, and John Nisbit for their help and patience. I thank Alex Palamarchuk, Vadim Maximov and Alexey Efanov for helping me learn new techniques initially, and for their assistance. I thank Natalya Nazaryan and Shruthi Sampath for helping me when I injured my foot. I also thank all my friends, and other members of the Croce lab for their help, and for making my years in the lab and in Columbus pleasant and memorable. I‟d like to thank Vidhya Ramachandran for being a great friend throughout my stay in Columbus. I would like to thank my aunt and uncle, Drs. Shobha and Manohar Ratnam, and my brother-in-law Sunil Iyengar, for helping me upon my arrival to Columbus, and for their constant advice and encouragement. v I thank my fiancé, Anand Ramanathan for preventing me from procrastinating the writing of my dissertation. I also thank him for dialing my number when he got to the US, and for his continued love and support. Finally, I would like to thank my parents, Poornima and K. Santanam, and sister, Dr. Kavita Iyengar, who have made me the person I am today. I owe all my accomplishments to them. Thank you. Urmila Santanam vi Vita 1997................................................................Sophia High School, Bangalore, India 1999................................................................Pre-University, Mount Carmel College, Bangalore, India. 2002................................................................B.S. Microbiology, Chemistry and Zoology St. Joseph‟s College, Bangalore, India. 2004 ...............................................................Graduate Research Associate, MCDB Program, The Ohio State University Publications “Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression.” Urmila Santanam, Nicola Zanesi, John P Hagan, Stefano Volinia, Hansjuerg Alder, Laura Rassenti, Thomas Kipps, Carlo M Croce and Yuri Pekarsky; PNAS. 2010 June 21; epub ahead of print. “Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181.” Yuri Pekarsky*, Urmila Santanam*, Amelia Cimmino, Alexey Palamarchuk, Alexey Efanov, Vadim Maximov, Stefano Volinia, Hansjuerg Alder, Chang-Gong Liu, Laura Rassenti, George Calin, John Hagan, Thomas Kipps and Carlo M. Croce; Cancer Res. 2006 Dec 15; 66(24):11590-3. (* Equal contribution) “13q14 deletions in CLL involve cooperating tumor suppressors.” Alexey Palamarchuk, Alexey Efanov, Natalya Nazaryan, Urmila Santanam, Hansjuerg Alder, Laura Rassenti, Thomas Kipps, Carlo M. Croce and Yuri Pekarsky; Blood 2010 May 13; 115(19):3916- 22. “Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL.” Yuri Pekarsky, Alexey Palamarchuk, Vadim Maximov, Alexey Efanov, vii Natalya Nazaryan, Urmila Santanam, Laura Rassenti, Thomas Kipps and Carlo M Croce; PNAS 2008 Dec 16; 105(50):19643-8. “Tal1 transgenic expression reveals absence of B-Lymphocytes.” Alexey Palamarchuk, Nicola Zanesi, Rami Aqeilan, Alexey Efanov, Vadim Maximov, Urmila Santanam, John Hagan, Carlo M. Croce and Yuri Pekarsky; Cancer Res 2006 Jun 15; 66:6014-17. Fields of Study Major Field: Molecular, Cellular and Developmental Biology viii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments............................................................................................................... v Vita .................................................................................................................................... vii List of Tables ..................................................................................................................... xi List of Figures ................................................................................................................... xii Chapter 1: Introduction ....................................................................................................... 1 B-cell chronic lymphocytic leukemia ............................................................................ 1 Tcl1 oncogene in B-CLL ............................................................................................. 12 microRNA .................................................................................................................... 14 Chapter 2: TCL1 expression in B-cell chronic lymphocytic leukemia is possibly regulated by miR-29 and miR-181 .................................................................................................... 28 Intruduction .................................................................................................................. 29 Materials and Methods ................................................................................................. 31 Results and Discussion ................................................................................................ 33 ix Chapter 3: B-Cell Chronic Lymphocytic Leukemia modeled in mouse by targeted miR-29 expression ......................................................................................................................... 47 Introduction .................................................................................................................. 48 Results .........................................................................................................................
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