Grønbæk Group – University of Copenhagen

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Grønbæk Group

Kirsten Grønbæk is a senior consultant and professor in clinical hematology at the Department of Hematology in Rigshospitalet, University of Copenhagen. She is the main clinical responsible for the treatment of patients with Myelodysplastic Syndrome (MDS). In addition she is affiliated professor and group leader at BRIC, where she leads a research lab. She is a principal investigator in the “Program for Translational Hematology” (PTH), which is a collaboration between University of Copenhagen, (Biotech Research and Innovation Centre (BRIC) and Danstem) and the Department of Hematology, Rigshospitalet.

A main focus of the Grønbæk group is molecular aberrations in MDS, with a particular focus on the pre-MDS phase. Patients are often referred with cytopenia, the cause of which remains unknown after standard diagnostic work up. These patients were previously followed for years with no definite diagnosis, however recent studies from the Grønbæk group and others show that around half of these patients have clonal hematopoiesis (i.e. clonal cytopenia of undetermined significance, CCUS)1. Although these mutated cells may be excellent candidates for being pre-cancer stem cells (CSCs) additional work is required to understand this. It is still unclear why some patients with CCUS develop overt MDS/AML, while others stay cytopenic with no disease progression for years. It is clear that additional mutations in classical tumor suppressors and oncogenes are generally required for disease progression; however, whether other factors such as germline genetics, immune mechanisms, and life style play a role is still unclear. Together with the other members of PTH and the van Andel Research Institute, Stand up to Cancer, Epigenetics Dream Team, the Grønbæk group is currently exploring these mechanisms, with a particular focus on whether the progression of CCUS can be prevented or postponed. Our first studies focus on the role of vitamin C and its potential for rescuing TET2 deficiency, which we are currently perusing in clinical/translational trials.2,3

Another focus in the Grønbæk group is the biology of mantle cell lymphoma (MCL). The Department of Hematology at Rigshospitalet has a long standing tradition for designing and implementing clinical trials in the context of the Nordic MCL group 4. The Grønbæk group has taken the lead in biological studies5, and we have recently identified a high-risk subgroup of patients with TP53 mutated MCL, who do not at all benefit from the current standard of 6,7.We are currently sequencing consecutive samples and relapse cases to further explore the cause of late relapses in MCL.

In both MDS and MCL we are currently establishing mouse models to further study the biological back ground for these diseases in collaboration with the basic scientist at BRIC.

Selected publications

1. Hansen JW, Westman MK, Sjö LD, et al. Mutations in idiopathic cytopenia of undetermined significance assist diagnostics and correlate to dysplastic changes. Am J Hematol. 2016;91(12):1234-1238. doi:10.1002/ajh.24554.

2. Liu M, Ohtani H, Zhou W, et al. Vitamin C increases viral mimicry induced by 5-aza-2’-deoxycytidine. Proc Natl Acad Sci U S A. 2016;113(37):10238-10244. doi:10.1073/pnas.1612262113.

3. Gillberg L, Ørskov AD, Liu M, Harsløf LBS, Jones PA, Grønbæk K. Vitamin C - A new player in regulation of the cancer epigenome. Semin Cancer Biol. November 2017. doi:10.1016/j.semcancer.2017.11.001.

4. Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175(3):410-418. doi:10.1111/bjh.14241.

5. Husby S, Ralfkiaer U, Garde C, et al. miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood. 2015;125(17):2669-2677. doi:10.1182/blood-2014-06-584193.

6. 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.

7. Jerkeman M, Eskelund CW, Hutchings M, et al. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Lancet Haematol. January 2018. doi:10.1016/S2352-3026(18)30018-8.