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Chronic Myeloid Leukemia
A high-content cytokine screen identifies myostatin propeptide as a positive regulator of primitive chronic myeloid leukemia cells
Ferrata Storti Foundation
Haematologica 2020 Volume 105(8):2095-2104
Sofia von Palffy,1 Niklas Landberg,1 Carl Sandén,1 Dimitra Zacharaki,2 Mansi Shah,3 Naoto Nakamichi,4 Nils Hansen,1 Maria Askmyr,1 Henrik Lilljebjörn,1 Marianne Rissler,1 Christine Karlsson,1 Stefan Scheding,2,5 Johan Richter,5 Connie J. Eaves,4 Ravi Bhatia,3 Marcus Järås1 and Thoas Fioretos1
1Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; 2Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden; 3Division of Hematology, Oncology and Bone Marrow Transplantation, University of Alabama at Birmingham, Birmingham, AL, USA;
4Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada and 5Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
ABSTRACT
Aberrantly expressed cytokines in the bone marrow (BM) niche are increasingly recognized as critical mediators of survival and expansion of leukemic stem cells. To identify regulators of primi- tive chronic myeloid leukemia (CML) cells, we performed a high-content cytokine screen using primary CD34+ CD38low chronic phase CML cells. Out of the 313 unique human cytokines evaluated, 11 were found to expand cell numbers ≥2-fold in a 7-day culture. Focusing on novel posi- tive regulators of primitive CML cells, the myostatin antagonist myo- statin propeptide gave the largest increase in cell expansion and was cho- sen for further studies. Herein, we demonstrate that myostatin propep- tide expands primitive CML and normal BM cells, as shown by increased colony-forming capacity. For primary CML samples, retention of CD34- expression was also seen after culture. Furthermore, we show expression of MSTN by CML mesenchymal stromal cells, and that myostatin propeptide has a direct and instant effect on CML cells, independent of myostatin, by demonstrating binding of myostatin propeptide to the cell surface and increased phosphorylation of STAT5 and SMAD2/3. In sum- mary, we identify myostatin propeptide as a novel positive regulator of primitive CML cells and corresponding normal hematopoietic cells.
Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by an acquired 9;22-chromosomal translocation in a hematopoietic stem cell (HSC) resulting in the expression of the BCR-ABL1 fusion protein.1 The BCR-ABL1 fusion protein is a constitutively active tyrosine kinase and triggers a cascade of aberrant downstream signaling pathways leading to clonal outgrowth of CML cells and subsequent disease manifestation.1,2 There is growing evidence to sug- gest that primitive CML cells affect the bone marrow (BM) niche, contributing to deregulated cytokine levels.3 In CML, several pro-inflammatory cytokines, such as IL-6,4,5 IL-1b,6 and TNF-a,4 have been shown to be up-regulated in patient serum. Cytokines are essential for the function and maintenance of cells, and altered cytokine levels influence not only leukemic cells, but also the normal HSC within the BM. A pro-inflammatory environment is thought to provide a selective advan- tage for the leukemic stem cells (LSC).7 In CML and acute myeloid leukemia (AML), we and others have shown that IL-1 is a positive regulator of LSC, and blocking IL-1 signaling inhibits the LSC.8-10 By contrast, chronic exposure to IL-1
Correspondence:
SOFIA VON PALFFY
sofia.von_palffy@med.lu.se
THOAS FIORETOS
thoas.fioretos@med.lu.se
Received: February 26, 2019. Accepted: September 26, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2019.220434
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2095
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