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Johanna Ungerstedt group – Epigenetics in myeloid diseases

Back row: Matilda Kjellander, Sigita Venkute, Annika Voigt, middle row: Katarina Lyberg, Hani Abdulkadir Ali, Deepika Nair, front row: Johanna Ungerstedt, Kajsa Ax.

Ungerstedt lab is a translational hematology lab focusing on epigenetics and genetics in the pathobiology of myeloid hematological malignancies, especially chronic myelomonocytic leukemia and systemic mastocytosis, in search for prognostic tools and novel therapeutic targets.

A common feature of these diseases is an overall poor prognosis and no curative treatment options. Our goal is to identify novel treatment targets and initiate and facilitate clinical trials, in order to improve symptom control and prolong survival.

For the rare diagnosis Systemic Mastocytosis, we have a unique opportunity to include patients in clinical trials and collect samples, as JU is the responsible hematologist for Center of Excellence Systemic Mastocytosis, Karolinska University Hospital, and clinically manages a large part of SM patients in Sweden.

Research program

Focus area 1: Systemic Mastocytosis (SM)

SM is a care myeloid disease where almost all patients have a mutation (D816V) in the KIT tyrosine kinase receptor is, rendering mast cells constantly active. In most cases, patients experience an indolent disease with symptoms of mast cell activation that may per se be severe, but have a normal life expectancy. However, 10-15% of patients will have an aggressive course of disease with a survival of only 2-4 years. Thus, there is a large discrepancy in clinical course, and what factors determine the fate of indolent or aggressive, is largely unknown.

One main goal with our SM research is to map the genetic and epigenetic factors that contribute to determine the disease course and prognosis. By functional and structural comparison of healthy and SM cell subsets, we hope to identify novel treatment targets. We are also involved in clinical trials as well as epidemiological studies and work with disease awareness, as SM is likely underdiagnosed in Sweden. Our Center of Excellence SM collaborates closely with the second Center in Sweden at Akademiska Hospital in Uppsala, and with the European Competence Network on Mastocytosis (ECNM).

Focus area 2: Chronic Myelomonocytic Leukemia (CMML)

CMML is a heterogenous clonal myeloid stem cell disorder. The heterogeneity of disease has many aspects, one is that the life expectancy of a CMML patient is 1-120 months and there are no solid prognostic scores to predict who will be a longtime survivor and who will not, which is of course a considerable clinical problem.

Our projects focus on one hand on population based epidemiological studies of the Swedish and more in detail the Stockholm CMML patients, to understand the biology of disease and its connection to external and internal factors, e.g. inflammation. Our other focus is to conduct largescale molecular sequencing of both genetic profile (whole exome sequencing and transcriptome) and epigenetic profiles. We are also molecularly studying how inflammation is involved in initiation and progression of CMML, especially the role of dysfunctional monocytes and plasmacytoid dendritic cells.

Keywords: Epigenetics, chromatin, systemic mastocytosis, chronic myelomonocytic leukemia

Members

Johanna Ungerstedt, MD, PhD, Group leader

Associate Professor of Hematology, Specialist in Hematology and Internal Medicine. Holds a Clinical Cancer Research Position from Cancerfonden 2018-23. Johanna received a PhD at KI in 2003, went for post doc in cell biology at Memorial Sloan Kettering Cancer Center working with histone modifying drugs, and second post doc in Biochemistry, MBB, KI, whereafter she started her group in 2012.

Kajsa Ax, biomedical analyst.

Responsible for the Systemic Mastocytosis Biobank.

Matilda Kjellander, PhD student working on CMML genetics and inflammation, funded by a CSTP grant.

Matilda is currently finishing her final year of medical school.

Ebba Lundin, MD, PhD student

Ebba is a resident doctor in Hematology at Karolinska University Hospital. Her PhD project is molecular profiling of CMML and also the juvenile counterpart JMML, including a large cohort of patients in an international collaboration.

Annika Voigt, Masters student 2018-19, working on CMML epidemiology with focus on inflammation.

Linda Forsell, Masters student 2019, working on CMML epidemiology.

Alumni

Deepika Nair, finished her PhD in Ungerstedt lab in August 2018, with a thesis entitled ” Redox alterations in chronic inflammatory diseases; diabetes, kidney failure and cancer”

https://openarchive.ki.se/xmlui/handle/10616/46350

Hani Abdulkadir Ali, finished her PhD in Ungerstedt lab in December 2018, with a thesis entitled ”Exploring the role of epigenetic alterations in myeloid malignancies with focus on drug response”.

https://ki.se/en/medh/calendar/dissertation-hani-abdulkadir-ali

Katarina Lyberg, post doc in Ungerstedt lab 2017-18, working on genetics and epigenetics in systemic mastocytosis, and treatment with histone modifying drugs.

Katarina has now left the lab for a second post doc in Sidinh Luc lab, HERM, KI.

Eunice Sindhuvi.E, Ph.D. visiting scientist in Ungerstedt lab in 2015, on a Linnaeus Palme teaching exchange program. Dr Sindhuvi is an Associate Professor at the Department of Haematology,Christian Medical College, Vellore, India

Financial support

  • The Swedish Cancer Society (Cancerfonden) Junior Clinical Research Position 6 years 2018-23 for J Ungerstedt
  • The Swedish Cancer Society (Cancerfonden)
  • Stockholm Cancer Association (Radiumhemmets Forskningsfonder)
  • KI Clinical Scientist Training Program (CSTP) salary funding for PhD of Matilda Kjellander 2017-2022
  • CIMED joint project grant with dr Sidinh Luc

Selected publications

Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells.
Grootens J, Ungerstedt JS, Nilsson G, Dahlin JS.
Blood Adv. 2018 Sep 11;2(17):2273-2281

Epigenetic Modifiers in Myeloid Malignancies: The Role of Histone Deacetylase Inhibitors.
Ungerstedt JS. Int J Mol Sci. 2018 Oct 9; 19(10):1-18

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels.
Nair D, Rådestad E, Khalkar P, Diaz-Argelich N, Schröder A, Klynning C, Ungerstedt J, Uhlin M, Fernandes AP.
Front Oncol. 2018 Sep 28;8: 407:1-12

Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia: A genome wide epigenetic analysis.
Khalkar P, Ali HA, Codó P, Argelich ND, Martikainen A, Arzenani MK, Lehmann S, Walfridsson J, Ungerstedt J, Fernandes AP.
Free Radic Biol Med. 2018 Mar; 117:247-257

Histone deacetylase inhibitor SAHA mediates epigenetic silencing of KIT D816V mutated systemic mastocytosis primary mast cells and selective apoptosis of mutated mast cells.
K Lyberg, H Abdulkadir Ali, J Grootens, M Tirfing, H Hägglund, G Nilsson, J S Ungerstedt Oncotarget 2017 Feb 7;8(6):9647-9659

Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease
M Tobiasson, H Abdulkadir, A Lennartsson, S Katayama, F Marabita, A De Paepe, MKarimi, K Krjutskov, E Einarsdottir, M Grövdal, M Jansson, A Ben Azenkoud, L Corddedu, S Lehmann, K Ekwall, J Kere, E Hellström-Lindberg, J Ungerstedt
Oncotarget. 2017 Apr 25;8(17):28812-28825

KIT signaling is dispensable for human mast cell progenitor development.
Dahlin JS, Ekoff M, Grootens J, Löf L, Amini RM, Hagberg H, Ungerstedt JS, Olsson-Strömberg U, Nilsson G.
Blood. 2017 Blood. 2017 Oct 19; 130 (16):1785-1794

Detection of circulating mast cells in advanced systemic mastocytosis
Dahlin JS, Ungerstedt JS, Grootens J, Sander B, Gülen T, Hägglund H, Nilsson G. Leukemia. 2016 Sep; 30 (9):1953-6

Mutations in Histone modulators are associated with prolonged survival during Azacitidine therapy M Tobiasson, D McLornan, M Karimi, M Dimitriou, M Jansson, A Ben Azenkoud, M Jädersten, G Lindberg, H Abdulkadir, A Kulasekarara, J Ungerstedt, A Lennartsson, K Ekwall, G J Mufti, E Hellström-Lindberg Oncotarget. 2016 Apr 19;7 (16):22103-15

Azacitidine induces profound genome-wide hypomethylation in primary myelodysplastic bone marrow cell cultures
Grövdal M, Karimi M, Nikpour M, Tobiasson M, Johansson LM, Luttropp K, Jansson M, Forsblom AM, Ekwall K, Lennartsson A, Ungerstedt J, Kere J, Greco D, and Hellström-Lindberg E. Leukemia2014 Feb 28(2):411-13