Modeling Shwachman-Diamond Syndrome Noemi Angela Zambetti PDF
Preview Modeling Shwachman-Diamond Syndrome Noemi Angela Zambetti
Deconstructing Niche Contributions to Leukemogenesis: Modeling Shwachman-Diamond Syndrome Noemi Angela Zambetti Deconstructing Niche Contributions to Leukemogenesis: Modeling Shwachman-Diamond Syndrome De beenmerg micro-omgeving in het ontstaan van leukemie: Shwachman-Diamond syndroom als model-ziekte. Doctoral dissertation to obtain the degree of Doctor from the Erasmus University Rotterdam by command of the rector magnificus Prof.dr. H.A.P. Pols Deconstructing Niche Contributions to Leukemogenesis: Modeling Shwachman-Diamond Syndrome Copyright © 2016 Noemi Angela Zambetti, Rotterdam, The Netherlands and in accordance with the decision of the Doctorate Board. The public defense shall be held on No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission from the author or, when appropriate, from the publishers Wednesday, 13 April 2016, at 13:30 hours of the publications. by ISBN: 978-94-6299-296-2 Noemi Angela Zambetti Cover: Noemi Zambetti and Ridderprint BV, Ridderkerk, The Netherlands born in Bari, Italy Layout and printing: Ridderprint BV, Ridderkerk, The Netherlands The work described in this thesis was performed at the Department of Hematology of the Erasmus Medical Center, Rotterdam, The Netherlands. The work was funded by grants from the Dutch Cancer Society (KWF Kankerbestrijding), the Netherlands Organization of Scientific Research (NWO), and the Netherlands Genomics Initiative. Printing of this thesis was financially supported by the Erasmus University Rotterdam. Deconstructing Niche Contributions to Leukemogenesis: Modeling Shwachman-Diamond Syndrome De beenmerg micro-omgeving in het ontstaan van leukemie: Shwachman-Diamond syndroom als model-ziekte. Doctoral dissertation to obtain the degree of Doctor from the Erasmus University Rotterdam by command of the rector magnificus Prof.dr. H.A.P. Pols Deconstructing Niche Contributions to Leukemogenesis: Modeling Shwachman-Diamond Syndrome Copyright © 2016 Noemi Angela Zambetti, Rotterdam, The Netherlands and in accordance with the decision of the Doctorate Board. The public defense shall be held on No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission from the author or, when appropriate, from the publishers Wednesday, 13 April 2016, at 13:30 hours of the publications. by ISBN: 978-94-6299-296-2 Noemi Angela Zambetti Cover: Noemi Zambetti and Ridderprint BV, Ridderkerk, The Netherlands born in Bari, Italy Layout and printing: Ridderprint BV, Ridderkerk, The Netherlands The work described in this thesis was performed at the Department of Hematology of the Erasmus Medical Center, Rotterdam, The Netherlands. The work was funded by grants from the Dutch Cancer Society (KWF Kankerbestrijding), the Netherlands Organization of Scientific Research (NWO), and the Netherlands Genomics Initiative. Printing of this thesis was financially supported by the Erasmus University Rotterdam. DOCTORAL COMMITTEE Supervisor: Prof.dr. I.P. Touw Other members: Prof.dr. H.R. Delwel Prof.dr. J.N.J. Philipsen Dr. M.M. von Lindern Co-supervisor: Dr. H.G.P. Raaijmakers To Francesco Gensano, dear friend and inspiring researcher. Your University fellows miss you dearly. DOCTORAL COMMITTEE Supervisor: Prof.dr. I.P. Touw Other members: Prof.dr. H.R. Delwel Prof.dr. J.N.J. Philipsen Dr. M.M. von Lindern Co-supervisor: Dr. H.G.P. Raaijmakers To Francesco Gensano, dear friend and inspiring researcher. Your University fellows miss you dearly. TABLE OF CONTENTS Chapter 1 General introduction 9 Chapter 2 Deficiency of the ribosome biogenesis gene Sbds in hematopoietic 43 stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes Chapter 3 Mesenchymal inflammation induces genotoxic stress in hematopoietic 73 stem and progenitor cells in leukemia predisposition syndromes Chapter 4 Low-risk myelodysplastic syndromes are characterized by a molecular 121 signature of mesenchymal stress and inflammation Chapter 5 Summary and general discussion 147 Addendum List of abbreviations 181 English summary 185 Dutch summary (Nederlands samenvatting) 189 Italian summary (Riassunto in italiano) 193 Curriculum vitae 197 PhD portfolio 199 Acknowledgements 201 TABLE OF CONTENTS Chapter 1 General introduction 9 Chapter 2 Deficiency of the ribosome biogenesis gene Sbds in hematopoietic 43 stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes Chapter 3 Mesenchymal inflammation induces genotoxic stress in hematopoietic 73 stem and progenitor cells in leukemia predisposition syndromes Chapter 4 Low-risk myelodysplastic syndromes are characterized by a molecular 121 signature of mesenchymal stress and inflammation Chapter 5 Summary and general discussion 147 Addendum List of abbreviations 181 English summary 185 Dutch summary (Nederlands samenvatting) 189 Italian summary (Riassunto in italiano) 193 Curriculum vitae 197 PhD portfolio 199 Acknowledgements 201 1 Chapter GENERAL INTRODUCTION 1. NORMAL HEMATOPOIESIS The blood of vertebrates is composed of different cell types that circulate in a fluid extracellular matrix called plasma. These cell types comprise erythrocytes (or red blood cells, RBC), that provide O2/CO2 transport, thrombocytes (or platelets, PLT), involved in hemostasis, and leukocytes (white blood cells, WBC), which protect the organism from infections. The lifespan of most blood cells is short compared to the organism they supply, with certain WBC populations having a half-life of 5 hours or less.1 The lifelong production of new blood cells, or hematopoiesis, is guaranteed by a pool of pluripotent cells that in adult mammals reside in the bone marrow (Figure 1). These cells, referred to as hematopoietic stem cells (HSCs), are able to divide and generate both differentiation-committed cells (called progenitors) and other pluripotent HSCs, virtually identical to the parent cell, which will preserve the hematopoietic capacity of the bone marrow over time. Proof that a single HSC can both differentiate and self-renew has been provided in different vertebrate models, showing that asymmetrical division of HSCs results from the specific orientation of cell fate determinants relative to the mitotic spindle.2-4 However, in homeostatic conditions most HSCs are not actively dividing, but rather preserved in a quiescent state, which is believed to be essential to maintain the genetic integrity of HSCs.5 The differentiation of HSCs into mature blood cells occurs in a multistep process in which lineage maturation is associated with progressive restriction of multi-lineage cell potential. HSCs first differentiate into multipotent progenitors (MPPs), which lack self-renewal capacity but retain multi-lineage potential. MPPs further differentiate into oligopotent progenitors, namely the common lymphoid progenitor (CLP) and the common myeloid progenitor (CMP). CLPs are required to produce lymphoid cells, including natural killer (NK) cells, B and T lymphocytes and immature plasmacytoid dendritic cells (DC), which will complete their maturation outside of the blood stream. CMPs, on the other hand, differentiate into either megakaryocyte-erythroid progenitors (MEPs) or granulocyte-macrophage progenitors (GMPs). MEPs can further differentiate into RBCs or megakaryocytes (from which PLTs are produced), whereas GMPs give rise to immature myeloid DCs, monocytes/macrophages and granulocytes. The latter are immune cells characterized by the presence of cytoplasmic granules. Based on how such granules react to histochemical dyes (e.g. May-Grünwald-Giemsa or Wright’s staining), granulocytes are further classified into basophils, eosinophils and neutrophils.6 Neutrophil maturation Neutrophilic granulocytes, or neutrophils, represent the most abundant WBC in the human blood and play a central role in the innate immune system, representing the first line of defense in the acute phase of inflammation. In response to chemotactic stimuli, neutrophils migrate from the
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