Johanna Ungerstedt group – Chronic myeloid malignancies

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.

Johanna Ungerstedt's research group. Photo: Private

A common feature of myeloid hematological malignancies, especially chronic myelomonocytic leukemia and systemic mastocytosis, 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.

About our research

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 long-time 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 large scale 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

Group leader

Johanna Ungerstedt

Associate Professor of Hematology, Specialist in Hematology and Internal Medicine.

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.

Holds a Clinical Cancer Research Position from Cancerfonden 2018-23.

Group members

Kajsa Ax

Biomedical analyst. Lab manager.

Responsible for biobanking of clinical samples and for the Systemic Mastocytosis biobank.

Matilda Kjellander

MD. PhD student.

MD, AT doctor. PhD student working on CMML genetics and epidemiological studies, funded by a CSTP grant.

Ebba Lundin

MD. Resident in Hematology. PhD student.

Ebbas PhD project is on autoimmune and inflammatory aspects of CMML including disturbances in the bone marrow microenvironment.

Stina Söderlund

MD. Specialist in Hematology. Post doc.

Stina is a clinical hematologist at Akademiska Hospital in Uppsala. Her post doc in Ungerstedt group focuses on immune aspects and plasma proteomics of systemic mastocytosis.

Liselotte Vesterlund

MD, PhD. Researcher.

Affiliated to Ungerstedt group.

Alumni

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.

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

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.

Research 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
  • Svenska Läkaresällskapet, post doc project funding for Stina Söderlund

Selected publications

Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelomonocytic Leukemia: Clinical and Molecular Genetic Prognostic Factors in a Nordic Population.
Wedge E, Hansen JW, Dybedal I, Creignou M, Ejerblad E, Lorenz F, Werlenius O, Ungerstedt J, Holm MS, Nilsson L, Kittang AO, Antunovic P, Rohon P, Andersen MK, Papaemmanuil E, Bernard E, Jädersten M, Hellström-Lindberg E, Grønbæk K, Ljungman P, Friis LS. Transplant Cell Ther 2021 Dec;27(12):991.e1-991.e9

Prognostic scoring systems and comorbidities in chronic myelomonocytic leukaemia: a nationwide population-based study.
Moreno Berggren D, Kjellander M, Backlund E, Engvall M, Garelius H, Lorenz F, Nilsson L, Rasmussen B, Lehmann S, Hellström-Lindberg E, Jädersten M, Ungerstedt J, Ejerblad E. Br J Haematol 2021 02;192(3):474-483

Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: a retrospective cohort study.
Pleyer L, Leisch M, Kourakli A, Padron E, Maciejewski JP, Xicoy Cirici B, Kaivers J, Ungerstedt J, Heibl S, Patiou P, Hunter AM, Mora E, Geissler K, Dimou M, Jimenez Lorenzo MJ, Melchardt T, Egle A, Viniou AN, Patel BJ, Arnan M, Valent P, Roubakis C, Bernal Del Castillo T, Galanopoulos A, Calabuig Muñoz M, Bonadies N, Medina de Almeida A, Cermak J, Jerez A, Montoro MJ, Cortés A, Avendaño Pita A, Lopez Andrade B, Hellstroem-Lindberg E, Germing U, Sekeres MA, List AF, Symeonidis A, Sanz GF, Larcher-Senn J, Greil R. Lancet Haematol 2021 Feb;8(2):e135-e148

Localization-Specific Expression of CCR1 and CCR5 by Mast Cell Progenitors.
Salomonsson M, Dahlin JS, Ungerstedt J, Hallgren J. Front Immunol 2020 Feb;26(11):321

Demonstration of human mast cell progenitors in the bone marrow.
Salomonsson M, Ungerstedt J, Alvarado-Vazquez PA, Hallgren J. Allergy 2020 02;75(2):456-460

Deciphering the differentiation trajectory from hematopoietic stem cells to mast cells.
Grootens J, Ungerstedt JS, Nilsson G, Dahlin JS. Blood Adv 2018 09;2(17):2273-2281

Epigenetic Modifiers in Myeloid Malignancies: The Role of Histone Deacetylase Inhibitors.
Ungerstedt JS. Int J Mol Sci 2018 Oct;19(10):3091

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.
Tobiasson M, Abdulkadir H, Lennartsson A, Katayama S, Marabita F, De Paepe A, Karimi M, Krjutskov K, Einarsdottir E, Grövdal M, Jansson M, Ben Azenkoud A, Corddedu L, Lehmann S, Ekwall K, Kere J, Hellström-Lindberg E, Ungerstedt J. Oncotarget 2017 Apr;8(17):28812-28825

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 09;30(9):1953-6