A main focus of the Grønbæk group is molecular aberrations in MDS, with a particular focus on the pre-MDS phase.
The overall vision is to improve the survival of patients with blood cancers through the integration of basic and clinical research.
To better understand the complexity of hematological cancer, we seek an in-depth understanding of the molecular background of these diseases. In the Grønbæk group we specifically investigate the role and interaction between genetics and epigenetics in the origin and evolution of hematological cancer.
Our main focus is on myelodysplastic syndrome (MDS), particularly on the pre-MDS phase and the early mutations in hematopoietic stem cells, that may lead to MDS. Another focus is the biology of mantle cell lymphoma (MCL).
Clonal hematopoiesis (CHIP) and early MDS
- A genetic predisposition to clonal hematopoiesis is not detectable in a cohort of 594 elderly twins.
- CHIP mutations are not associated with mortality in a direct comparison among discordant twin pairs.
- CHIP mutations in DNA repair genes predict poor prognosis in lymphoma patients that undergo autologous stem cell transplantation
- CHIP mutations are present already before chemotherapy is initiated and evolve under the pressure of chemotherapy
- Structural aberrations are associated with poor survival in patients with clonal cytopenia of undetermined significance
Prognostic factors in MCL
- The intensified standard-of-care regimens for younger patients with MCL do not overcome the deleterious effects of TP53
- MCLs with TP53 mutations should be considered for alternative frontline treatment.
- miR-18b overexpression identified patients with poor prognosis in 2 large prospective homogenously treated MCL cohorts.
- miR-18b overexpression adds prognostic information to the MIPI-B prognosticator.
- A circular RNA expression signature predicts dismal outcome in Mantle Cell Lymphoma, even in TP53 wildtype cases.
Mechanisms and efficacy of hypomethylating agents
- Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-Azacytidine
- Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers
- Vitamin C enhances the biological effects of azacytidine
Investigator initiated clinical trials including correlative studies:
- EVI-2: Vitamin C in Patients With Low-Risk Myeloid Malignancies (NCT03682029)
- EVI-3: Combining Active and Passive DNA Hypomethylation (NCT03999723)
- Repurposing metformin as a leukemia-preventive drug in CCUS and LR-MDS
- Phase I/II study of guadecitabine with atezolizumab in advanced MDS or CMML (NCT02935361)
- Molecular mechanisms of MDS, with focus on early MDS and the role of the microenvironment
- Hereditary MDS
- Optimizing therapy of MDS
- Rational implementation of prognostic markers in CCUS and MDS
- Prognostic role of CHIP in lymphoma during therapy
- DNA methylation and CHIP in hematological cancer
- Circular RNA in Mantle Cell Lymphoma
In the Grønbæk group we have access to high quality patient material, cell sorting and biobanking through the PTH collaboration.
For the characterization of patient material we are using the following techniques: Whole genome sequencing, ATAC-sequencing, RNA sequencing and DNA methylation (whole genome and pyrosequencing), RoboSeb, ddPCR, FACS sorting, mouse models, development of patient derived xenograft models (PDX).
1) Hansen JW, Pedersen DA, Larsen LA, Husby S, Hjelmborg J, Favero F, Weischenfeldt J, Christensen K, Grønbæk K. Clonal hematopoiesis in elderly twins: concordance, discordance and survival. Blood. 2020 Jan 23;135(4):261-268. doi: 10.1182/blood.2019001793. PMID: 31697811.
2) Husby S, Favero F, Nielsen C, Sørensen B, Bæch J, Grell K, Hansen JW, Rodriguez-Gonzalez FG, Haastrup EK, Fischer-Nielsen A, Andersen P, Arboe B, Sækmose SG, Hansen PB, Christiansen I, Clasen-Linde E, Meldgaard L, Ebbesen LH, Segel EK, Josefsson P, Thorsgaard M, El-Galaly TC, Brown P, Weischenfeldt J, Larsen TS, Grønbæk K. Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: A national population-based cohort study. Leukemia. 2020 Mar 20. doi: 10.1038/s41375-020-0795-z. Online ahead of print. PMID: 32203146.
3) Eskelund CW, Husby S, Favero F, Klausen TW, Rodriguez-Gonzalez FG, Kolstad A, Pedersen LB, Räty RK, Geisler CH, Jerkeman M, Weischenfeldt J, Grønbæk K. Clonal hematopoiesis evolves from pre-treatment clones and stabilizes after end of chemotherapy in patients with MCL. Blood. 2020 May 28;135(22):2000-2004. doi: 10.1182/blood.2019003539. PMID: 32181815.
4) Mikkelsen SU, Safavi S, Dimopoulos K, O’Rourke CJ, Andersen MK, Holm MS, Marcher CW, Andersen JB, Hansen JW, Grønbæk K. Structural aberrations are associated with poor survival in patients with clonal cytopenia of undetermined significance. Haematologica. 2020 Nov 12;Online ahead of print. doi: 10.3324/haematol.2020.263319 PMID: 33179473.
5)Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130(17):1903-1910. doi:10.1182/blood-2017-04-779736.
6) Ohtani H, Ørskov AD, Helbo AS, Gillberg L, Liu M, Zhou W, Ungerstedt J, Hellstrom-Lindberg E, Sun W, Liang G, Jones PA, Grønbæk K. Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity are Linked to Clinical Responses to 5-Azacytidine. Cancer Res. 2020 Jun 15;80(12):2441-2450. doi: 10.1158/0008-5472.CAN-19-1696. PMID: 32245794.
CAG i translationel hæmatologi får vokseværk med stor bevilling på 20 mio. til behandling af blodkræft
By Rigshospitalet, 20.01.2020
By Rigshospitalet, 29.06.2018
Regional and national collaboration on the targeted treatment of patients with blood cancer.
- Van Andel Research Institute, Stand Up to Cancer, Epigenetics Dream Team
International collaboration striving to design and conduct scientifically based clinical trials on epigenetic therapy.
Nordic collaboration on MDS trials and correlative studies.
Nordic collaboration on lymphoma trials and correlative studies.
Major funding sources:
- Novo Nordisk Fonden
- Kræftens Bekæmpelse
- Van Andel Research Institute, Stand Up To Cancer
- Rigshospitalets Forskningspuljer
- Region Hovedstadens Forskningsfond
- European Hematology Association (EHA)
- Danmarks Frie Forskningsråd - FSS