Studies of Ligands and Receptors Regulating Acute Myeloid Leukemia
Author
Summary, in English
To find selective regulators of leukemia cells, in article I, we performed an in vitro cytokine screen using AML and normal bone marrow cells. We identified interleukin 4 (IL4) as a selective negative regulator of AML cells, and showed that IL4 induces apoptosis of AML cells in a Stat6-dependent manner. By using two in vivo approaches, injections of IL4 into leukemic mice and enforced expression of IL4 by leukemia cells, we showed that IL4 reduced the leukemia burden and increased survival, suggesting that IL4 has therapeutic potential in AML.
In article II, we found that Toll-like receptor 1 (TLR1) is upregulated on the surface of AML cells compared to normal bone marrow cells. Agonistic stimulation of the TLR1/TLR2 complex with the synthetic lipopeptide PAM3CSK4 triggered NFκB-dependent differentiation and p38 MAPK-dependent apoptosis of AML cells. Upon transplantation of human and murine PAM3CSK4-treated AML cells, mice survived longer and had decreased leukemia cell numbers in the bone marrow compared to controls. Hence, agonistic stimulation of TLR1/TLR2 has therapeutic potential in AML.
In article III, we performed a cytokine screen using murine AML cells with an in vivo readout of leukemia-initiating activity using arrayed molecular barcoding. To this end, we developed lentiviral barcodes that allowed for in vivo competition of treated leukemia cells that could be traced to separate cytokine stimulations. We identified TNFSF13 as a positive regulator of AML-initiation, and showed that TNFSF13 suppresses apoptosis and promotes NFkB-dependent cell cycling. TNFSF13 is secreted by mature myeloid cells, suggesting a supporting role of these cells in AML initiation.
In article IV, we further investigated the anti-leukemic effects of IL4 in vivo and found that IL4 expands F4/80+ macrophages that kill AML cells. These macrophages showed a gene expression signature enriched for phagocytosis. Accordingly, in macrophage differentiation cultures with IL4, increased phagocytosis of AML cells was observed. Moreover, combined blockade of the cell surface molecule CD47 and IL4 stimulation resulted in enhanced macrophage-mediated phagocytosis of AML cells, revealing a new immunotherapeutic opportunity in AML.
In conclusion, this thesis has identified critical interactions between receptors on AML cells and ligands in the microenvironment, findings that might translate into new therapies in AML.
Department/s
- Division of Clinical Genetics
- Targeted therapies in leukemia
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2018
Language
English
Publication/Series
Lund University, Faculty of Medicine Doctoral Dissertation Series
Volume
2018
Issue
114
Full text
Document type
Dissertation
Publisher
Lund University: Faculty of Medicine
Topic
- Medical and Health Sciences
- Cancer and Oncology
Status
Published
Research group
- Targeted therapies in leukemia
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-682-3
Defence date
21 September 2018
Defence time
09:00
Defence place
Belfragesalen, BMC D15, Klinikgatan 32 i Lund
Opponent
- Jan-Henning Klusmann (professor)