Delwel Lab
Abnormal gene expression in acute myeloid leukemia
Ruud (H.R.) Delwel
E-mail: h.delwel@erasmusmc.nl
X: @RuudDelwel
Scopus: link
PubMed: link
LinkedIn: link
Contact:
Tessa Mannee, secretary, t.mannee@erasmusmc.nl
After his Biology study at Leiden University (1977 -1983), Ruud Delwel started his PhD research program in 1983 at the Dr. Daniel den Hoed Cancer Center in Rotterdam, under the supervision of Professor Bob Löwenberg. He graduated in 1990 (with honours) at the Erasmus University. The title of his thesis was, “Characterization of human acute myeloid leukemia progenitor cells”. He was a postdoctoral Fellow (1991-1992) at St. Jude’s Children’s Hospital, Memphis, Tennessee (Dr. James Ihle), applying retroviral insertional mutagenesis as a tool to uncover novel mechanisms of leukemic transformation. He obtained a Fellowship from the Royal Dutch Academy of Science (KNAW ) in 1994. Since 2010, Ruud Delwel is Professor Molecular Leukemogenesis at the Hematology department of Erasmus MC. In 2015 he was rewarded with the Dutch Cancer Research (KWO) Price and in 2017 he received the Jose Carreras Award in Madrid at the annual meeting of the European Hematology Association. In 2021 he was chair of the scientific program of the EHA in Vienna. In the past two decades his science had a focus on “Understanding of the molecular mechanisms of malignant transformation in acute myeloid leukemia (AML)", with a particular focus on epigenetic alterations and abnormal gene regulation.
The important discoveries his team made were:
- That AML subtypes can be recognized by unique gene expression and DNA methylation signatures
- A marker for poor prognosis in AML: abnormal expression of the EVI1 gene
- A novel mechanism of abnormal gene regulation in AML: Enhancer-hijacking, driving aberrant expression of EVI1
- That the transcription factor gene CEBPA is frequently mutated at both alleles in AML (CEBPAdm AML)
- And that those CEBPAdm AMLs have a favorable prognosis
- Discovery of a unique regulatory element among 14 enhancers to be the driver of CEBPA expression in myeloid cells
Our research
We study mechanisms of aberrant gene expression leading to leukemic transformation of myeloid progenitor cells in the bone marrow. Those studies have increased our understanding of the molecular biological mechanisms of associated with the distinct subtypes of acute myeloid leukemia (AML). Each subtype can be distinguished from others based on unique gene expression and epigenetic signatures. Most subgroups are associated with very specific gene mutations, such as in CEBPA or in EVI1.
In the last decade our research has been directed more and more towards understanding of the mechanisms of transformation of one specific subtype, i.e. AML with chromosome 3q26 rearrangements leading to overexpression of the EVI1 gene. In 2014 (Groschel et al, Cell 2014) we discovered a new mechanism of transformation in AML with inv(3)(q21;q26) or t(3;3)(q21:q26). In each patient within this group we found that a unique enhancer of the gene called GATA2 (located at chromosome 3q21) had translocated to EVI1 (at 3q26), leading to the overexpression of EVI1. This translocation also resulted in GATA2 haploinsifficiency, due to the loss of its enhancer. In particular this led to the discovery that the hijacked enhancer changed into a hyperactive oncogenic super enhancer (OSE) with specific binding and activation of critical transcription factors (Smeenk et al, Cancer Discovery 2021). We identified many more OSEs hijacked by EVI1 in other 3q26 rearranges AMLs and demonstrated the importance of enhancer to promoter looping and the importance of CTCF sites for this interaction (Ottema et al, Nature Comm. 2021). We have generated multiple cell line models in which we tagged EVI1 with a GFP molecule, in order to study the mechanism of EVI1 expression using flow cytometry. By applying different CRISPR mediated genome editing approaches or by exposing the cells to small molecules we study ways to turn off the expression of the transforming oncogene EVI1 in AML. The outcome of these studies will help us to identify molecules able to interfere with leukemic cells growth driven by EVI1.
Our team
Ruud Delwel, principal investigator
Claudia Erpelinck-Verschueren, research technician
Marije Havermans, research technician
Stanley van Herk, research technician
Leonie Smeenk, postdoc
Emma Boertjes, PhD student
Juliëtte Engelberts, PhD student
Dorien Pastoors, PhD student
Shivani Rajhansa, PhD student
Nynke Meesters, intern
Willem Teunissen, intern
Key publications
Stefan Gröschel, Mathijs A. Sanders, Remco Hoogenboezem, Elzo de Wit, Britta A.M. Bouwman, Claudia Erpelinck, Marije Havermans, Roberto Avellino, Konstanze Döhner, H. Berna Beverloo, James E. Bradner, Hartmut Döhner, Bob Löwenberg, Peter J.M. Valk, Eric M.J. Bindels, Wouter de Laat and Ruud Delwel. An oncogenic enhancer-rearrangement causes concomitant deregulation of EVI1 and GATA2 in leukemia. Cell. 2014 Apr 10;157(2):369-81
Stefan Gröschel, Mathijs A. Sanders, Remco Hoogenboezem, Annelieke Zeilemaker, Marije Havermans, Claudia Erpelinck, Eric M.J. Bindels, Bob Löwenberg, H. Berna Beverloo, Hartmut Döhner, Konstanze Döhner, Ruud Delwel (shared last author), and Peter J. M. Valk. Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways. Blood. 2015 Jan 1;125(1):133-9.
Avellino R, Havermans M, Erpelinck C, Sanders MA, Hoogenboezem R, van de Werken HJ, Rombouts E, van Lom K, van Strien PM, Gebhard C, Rehli M, Pimanda J, Beck D, Erkeland S, Kuiken T, de Looper H, Gröschel S, Touw I, Bindels E, Ruud Delwel. An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation. Blood. 2016 Jun 16;127(24):2991-3003
Bas J. Wouters and Ruud Delwel. Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Review. Blood. 2016;127(1): 42-52.
Glass J, Hassane DC, Wouters B, Kunimoto H, Avellino R, Garrett-Bakelman FE, Guryanova OA, Bowman R, Redlich S, Intlekofer A, Meydan C, Qin T, Fall MP, Alonso A, Guzman ML, Valk PJ, Thompson CB, Levine RL, Elemento O, Ruud Delwel (shared last author), Melnick A, Figueroa ME. Epigenetic Identity in AML Depends on Disruption of Non-promoter Regulatory Elements and is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers. Cancer Discov. 2017 Aug;7(8):868-883
Sophie Ottema, Roger Mulet-Lazaro, H Berna Beverloo, Claudia Erpelinck, Stanley van Herk, Robert van der Helm, Marije Havermans Tim Grob Peter J M Valk Eric Bindels , Torsten Haferlach, Claudia Haferlach Leonie Smeenk, Ruud Delwel. Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia. Blood 2020 Jul 9;136(2):224-234.
Mulet-Lazaro R, van Herk S, Erpelinck C, Bindels E, Sanders MA, Vermeulen C, Renkens I, Valk P, Melnick AM, de Ridder J, Rehli M, Gebhard C, Ruud Delwel, Wouters BJ. Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML. Blood. 2021 Jul 15;138(2):160-177
Ottema S, Mulet-Lazaro R, Erpelinck-Verschueren C, van Herk S, Havermans M, Arricibita Varea A, Vermeulen M, Beverloo HB, Gröschel S, Haferlach T, Haferlach C, J Wouters B, Bindels E, Smeenk L, Ruud Delwel. The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops. Nat Commun. 2021 Sep 28;12(1):5679.
Leonie Smeenk, Sophie Ottema1, Roger Mulet-Lazaro, Anja Ebert, Marije Havermans, Andrea Arricibita Varea, Michaela Fellner, Dorien Pastoors, Stanley van Herk, Claudia E-rpelinck, Tim Grob, Remco Hoogenboezem, François G. Kavelaars, Daniel R. Matson, Emery H. Bresnick, Eric Bindels, Alex Kentsis, Johannes Zuber and Ruud Delwel. Selective requirement of MYB for oncogenic hyperactivation of a translocated enhancer in leukemia. Cancer Discov. 2021 Nov;11(11):2868-2883.
Atsushi Tanaka, Taizo A. Nakano, Masaki Nomura, Hiromi Yamazaki, Jan P. Bewersdorf, Roger Mulet-Lazaro, Simon Hogg, Bo Liu, Alex Penson, Akihiko Yokoyama, Weijia Zang, Marije Havermans, Miho Koizumi, Yasutaka Hayashi, Hana Cho, Akinori Kanai, Stanley C. Lee, Muran Xiao, Yui Koike, Yifan Zhang, Miki Fukumoto, Yumi Aoyama, Tsuyoshi Konuma, Hiroyoshi Kunimoto, Toshiya Inaba, Hideaki Nakajima, Hiroaki Honda, Hiroshi Kawamoto, Ruud Delwel, Omar Abdel-Wahab, Daichi Inoue. Aberrant EVI1splicing contributes to EVI1-rearranged leukemia. Blood. 2022 Aug 25;140 (8): 875–888.