Our research
Cancer typically develops through the sequential acquisition of genetic lesions targeted to cells in normal tissues. Although most cells have a short lifespan and gradually are lost over time, tissue-specific stem cells such as the hematopoietic stem cell, with ability to sustain throughout the lifespan of an individual are at particular risk for malignant transformation due to the random accumulation of DNA mutations.
Next-generation DNA sequencing has revealed the genetic architecture of myeloid malignancies and demonstrated that most chronic myeloid malignancies are driven by recurrent oncogenic mutations targeted to a limited number of genes. The same mutations can be detected in a large fraction of blood cells in healthy, elderly individuals, without any symptoms of hematologic disorders but with higher risk for later leukemic transformation, a condition referred to as clonal hematopoiesis (CH).
Our long-term goal is to exploit presence of somatic non-driver and driver mutations targeted to hematopoietic stem cells to provide new insight toward normal human hematopoietic stem cell biology, transformation allowing development of leukemic stem cells and develop strategies for therapeutic targeting of pre-leukemic and leukemic stem cells. This is achieved by combining advanced flow cytometry identification and isolation of distinct bone marrow hematopoietic stem and progenitor cells from healthy individuals and patients with leukemia, with DNA sequencing of for identification of somatic mutations. This allows for genetic fate mapping to monitor the contribution of mutations originating from hematopoietic stem cells to steady state hematopoiesis, as well as following stress and exposure to extrinsic cues by tracking changes in mutation contribution of human bone marrow cells transplanted into immune-compromised mice. Detailed cellular and molecular characterization of candidate leukemia propagating cells has also identified potential targets for therapeutic targeting, which is explored in in vitro and in vivo assays in combination with immune cell-based therapeutics. Collaborators include Sten Eirik Jacobsen (KI), Eva Hellström-Lindberg (KI), Johanna Ungerstedt (KI), Magnus Tobiasson (KI), Rickard Sandberg (KI), Sten Linnarsson (KI), Seishi Ogawa (Kyoto University), Adam Mead (University of Oxford), Johanna Olweus (University of Oslo).
Collaborators
Karolinska Institutet
- Sten Eirik W. Jacobsen, Department of Medicine, Huddinge
- Eva Hellström Lindberg, Department of Medicine, Huddinge
- Magnus Tobiasson, Department of Medicine, Huddinge
- Johanna Ungerstedt, Department of Medicine, Huddinge
- Stephen Malin, Department of Medicine, Solna
- Sten Linnarsson, Department of Medical Biochemistry and Biophysics
- Rickard Sandberg, Department of Cell and Molecular Biology
- Seishi Ogawa, Department of Pathology and Tumor Biology, Kyoto University and Karolinska Institutet
International collaborations
- Johanna Olweus, Department of Cancer Immunology, Oslo University Hospital
- Adam Mead, MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford
Research support
- Cancerfonden
- Radiumhemmets Forsknings Fonder
- Ming Wai Lau Centre for Reparative Medicine