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The interplay between microenvironmental signaling and novel targeted drugs in
CLL
Thijssen, R.
Publication date
2016
Document Version
Final published version
Link to publication
Citation for published version (APA):
Thijssen, R. (2016). The interplay between microenvironmental signaling and novel targeted
drugs in CLL.
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The inTerplay beTween
microenvironmenTal
signaling and novel
TargeTed drugs in cll
rachel Thijssen
R
a
chel Thijs
sen
The in Te Rpl a y be Tween mic Roenvi RonmenTal signaling and no
vel Ta Rge Ted d Rugs in cll
The inTerplay beTween
microenvironmenTal
signaling and novel
TargeTed drugs in cll
Lay out and printing: Off page, Amsterdam
Cover design: Bert Potse
ISBN: 978-94-6182-733-3
The printing of this thesis was financially supported by: AbbVie, Celgene, Gilead Sciences, MRC-Holland, Roche, Sanofi-Genzyme
Copyright © Rachel Thijssen, Amsterdam, The Netherlands
All right reserved. No part of this thesis may be reproduced or transmitted in any from or by any means without the written permission of the author.
THE INTERPLAY BETWEEN MICROENVIRONMENTAL SIGNALING
AND NOVEL TARGETED DRUGS IN CLL
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus
prof. dr. ir. K.I.J. Maex
ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel
op vrijdag 25 november 2016, te 14:00 uur
door
Rachel Thijssen
PROMOTIECOMMISSIE
Promotores
Prof. dr. E.F. Eldering Universiteit van Amsterdam Prof. dr. A.P. Kater Universiteit van Amsterdam
Copromotor
Prof. dr. M.J. Kersten Universiteit van Amsterdam
Overige leden
Prof. dr. M.H.J. van Oers Universiteit van Amsterdam Prof. dr. J. Borst Universiteit van Amsterdam Dr. M. Spaargaren Universiteit van Amsterdam Prof. dr. J.H. Veelken Universiteit Leiden
Prof. dr. R.W. Hendriks Erasmus Universiteit Rotterdam Faculteit der Geneeskunde
TABLE OF CONTENTS
Chapter 1 General Introduction 7
Chapter 2 The pan phosphoinositide 3-kinase/mammalian 21 target of rapamycin inhibitor SAR245409 (voxtalisib/XL765)
blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells
Chapter 3 Dual TORK/DNA-PK inhibition blocks critical signalling 51 pathways in chronic lymphocytic leukemia
Chapter 4 Targeting antigen-independent proliferation in chronic 83 lymphocytic leukemia through differential kinase inhibition
Chapter 5 Resistance to ABT-199 induced by microenvironmental signals 103 in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors
Chapter 6 IL-21 and IL-4 distinctly affect NF-
κ
B binding on the Bcl-XL 121 promoter in CLL cellsChapter 7 General Discussion 139
Appendices Summary 157 Samenvatting 161 Curriculum Vitae 164 Publications 165 PhD Portfolio 166 Dankwoord 168
