Table Of ContentDeconstructing 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
Description:developing acute myeloid leukemia is higher in patients affected by bone http://www.mds-foundation.org/wp-content/uploads/manual/ASH2014/
