The major research interests of the Porse group is to understand the gene regulatory mechanisms that governs the behavior of normal HSCs, myeloid lineage decision events during normal hematopoiesis and leukemic stem cells with the ultimate aim of identifying potential targets for future treatment of leukemia patients.
The Porse Group is located at the Finsen Laboratory, a cancer research department at the Finsen Centre at Rigshospitalet, Copenhagen University Hospital. Bo Porse is also a PI at the Danish Stem Cell Centre (DanStem) - funded by the Novo Nordisk Foundation
Detailed mechanistic insights into the gene regulatory networks governing the behavior of normal and malignant hematopoietic stem/progenitor cells (HSPCs) promise to uncover opportunities for translational approaches. Moreover, the analyses of these networks in both a normal and a leukemic context will synergize to forward our understanding of their functional importance. To address our overall research vision, the overarching goals of our research are to:
- Understand the gene regulatory mechanisms that governs the behavior of normal HSCs and myeloid lineage decision events during normal hematopoiesis
- Understand the gene regulatory mechanisms governing the behavior of leukemic stem and progenitor cells
- To use the knowledge gained from 1) and 2) to identify novel potential targets for future treatment of leukaemia. By working at the interface between normal and malignant hematopoiesis we will able to gain novel insights into both processes with the ambition to translate our findings for the benefit of future leukemia patients.
We have made novel discoveries improving our understanding of the molecular control governing normal and malignant haematopoiesis. In addition, we have developed relevant bioinformatics tools and pipelines for the processing of cancer transcriptome data. Finally, we have put major emphasis on the identification of novel oncogenic determinants using functional genetics aimed at the identification of novel therapeutic targets. Selected findings are described below.
- A Quantitative Single-Cell Proteomics Approach to Characterize an Acute Myeloid Leukemia Hierarchy. (Schoof et al. 2019, preprint in BioRxiv)
We developed a proof-of-concept protocol for robust analysis of the proteomes of single cells including a computational pipeline (SCeptre). The model system in this study was an acute myeloid leukemia cell culture system.
The role of C/EBPa in normal and malignant hematopoiesis
- We have identified C/EBPa to be a key collaborating transcription factor required for MLL-ENL induced leukemic transformation independent of differentiation stage, and uncovered a C/EBPa-dependent, MLL-ENL driven transcriptional program. Additionally, we found that C/EBPa was dispensable in already established leukemias (Ohlsson et al 2014, J Exp Med).
- We found that mutant C/EBPa directly drives the expression of the targetable tumor-promoting factor CD73 in AML (Jakobsen et al 2019, Sci Adv).
- We showed a novel and crucial role for C/EBPa in HSC maintenance (Hasemann et al. 2014 Plos Genet).
- We uncovered a role for C/EBPa as a pioneering factor at a subset of enhancers during granulocytIc differentiation (Pundhir et al. 2018, Cell Rep).
Transcriptional regulators in normal and malignant hematopoiesis
- We identified RBM25 as a tumor suppressor in AML and found that RBM25 regulates MYC activity, via its impact on the splicing of the MYC-inhibitor BIN1. RBM25 also regulates splicing of other genes including the apoptotic regulator BCL-X (Ge et al. 2019, Nat Commun).
- We have shown that ERG is essential for HSC function, and that its loss unleashes the inappropriate expression of MYC target genes resulting in differentiation of HSCs (Knudsen KJ et al. 2015, Genes Dev).
- We have also uncovered a novel and unexpected function for ERG in B-cell development where ERG controls two specific steps of this process, one of them being recombination within the Igh locus at the preB II stage (Søndergaard et al. 2019, Cell Rep).
The in vivo importance in nonsense mediated decay (NMD)
- We demonstrate that NMD regulates alternative splicing outcomes through an intricate web of splicing regulators and that its loss leads to the deregulation of a panoply of splicing events, providing novel insights into its role in core- and tissue-specific regulation of gene expression (Weischenfeldt et al. 2012, Genome Biol).
- Most of our projects are defined from a stem cell centric point of view and evolves around studying stem cells in both normal and malignant hematopoiesis.
- For many years a major focus for the Porse group has been to understand the role of the transcription factor C/EBPa in normal and malignant hematopoiesis. We use genetic screens, multi-omics approaches and murine model systems to study this.
- AML biology: We use transcriptome profiling and functional genetics to understand disease mechanisms and identify new targets for better treatment of patients.
- We use Single Cell Mass Spectrometry (scMS) in many project and are working hard to further develop and refine the method and use it for characterization of both normal and malignant hematopoietic cells.
Erwin M. Schoof, Nicolas Rapin, Simonas Savickas, Coline Gentil, Eric Lechman, James Seymour Haile, Ulrich auf dem Keller, John E. Dick, Bo T. Porse (2019). A Quantitative Single-Cell Proteomics Approach to Characterize an Acute Myeloid Leukemia Hierarchy. Preprint published in BioRxiv. doi:https://doi.org/10.1101/745679
Ge Y, Schuster MB, Pundhir S, Rapin N, Bagger FO, Sidiropoulos N, Hashem N, Porse BT. (2019) The splicing factor RBM25 controls MYC activity in acute myeloid leukemia. Nat Commun. 10(1):172. doi:10.1038/s41467-018-08076-y.
Jakobsen JS, Laursen LG, Schuster MB, Pundhir S, Schoof E, Ge Y, d'Altri T, Vitting-Seerup K, Rapin N, Gentil C, Jendholm J, Theilgaard-Mönch K, Reckzeh K, Bullinger L, Döhner K, Hokland P, Fitzgibbon J, Porse BT. (2019) Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML. Sci Adv. 5(7):eaaw4304. doi: 10.1126/sciadv.aaw4304
Ohlsson E, Hasemann MS, Willer A, Lauridsen FK, Rapin N, Jendholm J, Porse BT. (2014) Initiation of MLL-rearranged AML is dependent on C/EBPα. J Exp Med. 211(1):5-13. doi: 10.1084/jem.20130932.
Knudsen KJ, Rehn M, Hasemann MS, Rapin N, Bagger FO, Ohlsson E, Willer A, Frank AK, Søndergaard E, Jendholm J, Thorén L, Lee J, Rak J, Theilgaard-Mönch K, Porse BT. (2015) ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation. Genes Dev. 2015 Sep 15;29(18):1915-29. doi: 10.1101/gad.268409.115.
In the media
By Hæmatologisk Tidsskrift 29/09-2020
By Novo Nordisk Foundation 24/08-2017
Program for translational hematology (PTH)
PTH is a translational research program aiming at improving immediate and long-term outcome for hematological patients. Through interdisciplinary research basic researchers and clinicians are brought closer together and have a specific focus on uncovering the mechanism leading to hematopoietic malignancies, identifying new drug targets, strengthening the treatments and in particularly facilitating personalized treatment.
Bo Porse, DanStem/BRIC/Finsen, Professor and Director
Kristian Helin, DanStem/BRIC/MSKCC, Professor and Chair/Director
Kirsten Grønbæk, BRIC/Rigshospitalet, DanStem-affiliated, Professor, MD
Kim Theilgaard-Mönch, BRIC/Rigshospitalet, DanStem-affiliated, Associate Professor, MD
Krister Wennerberg, BRIC/Rigshospitalet, DanStem-affiliated, Professor
Kyoung-Jae Won, BRIC, DanStem-affiliated, Associate Professor
Svend Andersen Fonden