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Micrornas Link the Germinal Center Reaction and B Cell Lymphomagenesis

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Micrornas Link the Germinal Center Reaction and B Cell Lymphomagenesis Universidad Autónoma de Madrid Departamento de Bioquímica microRNAs link the Germinal Center reaction and B cell lymphomagenesis PhD Thesis Nahikari Bartolomé Izquierdo Madrid, 2016 Departamento de Bioquímica Facultad de Medicina Universidad Autónoma de Madrid microRNAs link the Germinal Center reaction and B cell lymphomagenesis Memoria presentada por la licenciada en Bioquímica Nahikari Bartolomé Izquierdo para optar al título de Doctor por la Universidad Autónoma de Madrid Directores de tesis: Dra. Almudena R. Ramiro Dra. Virginia García de Yébenes Este trabajo ha sido realizado en el laboratorio de Linfocitos B, en Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid, 2016 ABSTRACT Germinal centers (GC) are microstructures where B cells that have been activated by antigen undergo a developmental program that involves the somatic diversification of their immunoglobulin genes and intense proliferative activity coupled to apoptotic selective events. As a result, from GCs emerge plasma cells and memory B cells that bear immunoglobulins with higher affinity for the initi- ating antigen and with more versatile effector functions. While ensuring a competent humoral im- mune response, GCs are also a site particularly prone to neoplastic transformation. Indeed, the vast majority of human lymphomas arise from GC-experienced B cells. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post- transcriptionally. In the past years miRNAs have arisen as key regulators of the immune function, however little is known of their role in GC B cells. In this work, we have identified miR-217 and miR- 28 as GC microRNAs and have explored their functional impact in GC events and in B cell lym- phomagenesis. We observed that miR-217 is a positive modulator of the GC response that boosts immuno- globulin diversification, i.e. the generation of class-switched antibodies and the frequency of somatic hypermutation. We found that miR-217 dampens the expression of a DNA damage response and re- pair gene network and in turn stabilizes Bcl-6 expression in GC B cells. Importantly, miR-217 overex- pression also promotes mature B-cell lymphomagenesis; this is physiologically relevant as we find that miR-217 is overexpressed in aggressive human B-cell lymphomas. In contrast, miR-28 acts as a negative regulator of the GC response that impairs B cell prolifera- tion and survival through the regulation of a BCR signaling gene network. In addition, we found that miR-28 expression is lost in a wide range of GC-derived human malignancies. Further, miR-28 re- expression dramatically inhibits tumor growth in various lymphoma models, suggesting that miR-28 is a tumor suppressor for GC-derived neoplasias. Together, we have found that miR-217 and miR-28 provide antagonistic regulatory roles of the GC reaction that are intimately intertwined with pathways leading to B cell transformation. In addi- tion, our results open new perspectives for the development of a novel therapeutic strategy for the treatment of B cell tumors based on miR-28 replacement. 7 RESUMEN Los centros germinales (CG) son microestructuras donde las células B que han sido activadas por antígeno llevan a cabo un programa madurativo que implica la diversificación somática de los genes de inmunoglobulinas y una intensa actividad proliferativa asociada con procesos de selección apoptóticos. Como resultado, de los CG emergen células plasmáticas y células B memoria que portan inmunoglobulinas con mayor afinidad por el antigeno iniciador, y con mayor versatilidad funcional. Aunque aseguran la eficiencia de la respuesta inmune humoral, los CG son también un entorno parti- cularmente propenso a la transformación maligna. De hecho, la inmensa mayoría de los linfomas humanos tienen su origen en células B que han pasado por un CG. Los microRNAs (miRNAs) son moléculas de RNAs pequeñas y no codificantes que regulan la expresión génica post-transcripcionalmente. En los últimos años los miRNAs han surgido como regu- ladores clave de la función inmune, pero se sabe muy poco de su función en células B de CGs. En este trabajo hemos identificado a miR-217 y miR-28 como miRNAs de CG y hemos explorado su impacto funcional en los procesos asociados a CGs y a la linfomagénesis B. Observamos que miR-217 es un modulador positivo de la respuesta de CG que aumenta la di- versificación de anticuerpos, es decir, la generación de cambio de isotipo y la hipermutación somáti- ca. Encontramos que miR-217 amortigua la expresión de una red de genes implicados en la respuesta al daño y la reparación del DNA y a su vez estabiliza la expresión de Bcl-6 en células B de CG. Además, la sobreexpresión de miR-217 induce la generación de linfomas B; esta observación es relevante fisio- lógicamente porque encontramos que miR-217 está sobre-expresado en ciertos linfomas B humanos. Por el contrario, miR-28 actúa como un regulador negativo de la respuesta de CG, que dismi- nuye la proliferación y la supervivencia de las células B mediante la regulación de la señalización a través del BCR. También encontramos que la expresión de miR-28 se pierde en un amplio espectro de neoplasias derivadas de CGs. Finalmente, la re-expresión de miR-28 produce una inhibición dra- mática en el crecimiento tumoral en diversos modelos de linfoma, lo que sugiere que miR-28 es un supresor de tumores en neoplasias derivadas de CG. En conjunto, hemos encontrado que miR-217 y miR-28 tienen funciones antagónicas en la re- gulación del CG y que estas están íntimamente relacionadas con los mecanismos que dan lugar a la transformación de las células B . Además, nuestros resultados abren nuevas posibilidades para el desarrollo de estrategias terapéuticas para el tratamiento de linfomas B, basadas en la re-expresión de miR-28. 9 INDEX ABSTRACT/RESUMEN ....................................................................................................... 7-9 ABBREVIATIONS ................................................................................................................ 15 INTRODUCTION ................................................................................................................. 19 1. B cell differentiation and function .............................................................................. 19 1.1. Immune system: innate immunity and adaptive immunity ......................................... 19 1.2. B cell differentiation and antibody diversification ....................................................... 19 1.2.1- Early B cell differentiation and primary antibody diversification .......................... 20 1.2.2- The Germinal Center reaction and secondary antibody diversification ................ 20 1.3. The Germinal Center transcriptional program ............................................................. 22 1.4. B cell lymphomas ......................................................................................................... 24 1.4.1- Classification and etiology .................................................................................... 24 1.4.2- Oncogenic signaling .............................................................................................. 25 1.4.3- Transcriptional regulators and lymphomagenesis ................................................ 27 1.4.4- B cell lymphoma treatment ................................................................................... 28 2. miRNA control of B cell physiology ............................................................................. 29 2.1. Bases of miRNA biology ................................................................................................ 29 2.2. miRNA control of B cell function .................................................................................. 30 2.3. miRNAs in B cell lymphomagenesis ............................................................................. 32 2.4. miRNA mediated therapeutics ..................................................................................... 33 OBJECTIVES ....................................................................................................................... 37 MATERIALS AND METHODS ............................................................................................... 41 RESULTS ............................................................................................................................ 57 1. Role of miR-217 in Germinal Center reaction and in B cell lymphomagenesis ............... 59 1.1. miR-217 expression is upregulated in activated B cells ............................................... 59 1.2. Generation of B cell specific mouse models ................................................................ 59 1.3. miR-217 expression enhances the Germinal Center reaction ..................................... 61 1.4. Inhibition of endogenous miR-217 impairs the Germinal Center reaction in vivo ...... 64 1.5. miR-217 regulates a DNA damage response and repair gene network and stabilizes Bcl-6 expression in Germinal Center B cells ........................................................................ 66 1.5.1- Analysis of gene expression profile changes induced by miR-217 in Germinal Center B cells .............................................................................................................................. 66 1.5.2- Analysis of the DNA damage response and Bcl-6 expression in miR-217 over- expressing B cells upon genotoxic stress ........................................................................
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