A high-content cytokine screen identifies myostatin propeptide as a positive regulator of primitive chronic myeloid leukemia cells

Summary, in English

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 primitive chronic myeloid leukemia (CML) cells, we performed a high-content cytokine screen using primary CD34⁺ CD38^low 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 positive regulators of primitive CML cells, the myostatin antagonist myostatin propeptide gave the largest increase in cell expansion and was chosen for further studies. Herein, we demonstrate that myostatin propeptide 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 summary, we identify myostatin propeptide as a novel positive regulator of primitive CML cells and corresponding normal hematopoietic cells.

• Author: Sofia von Palffy; Niklas Landberg; Carl Sandén; Dimitra Zacharaki; Mansi Shah; Naoto Nakamichi; Nils Hansen; Maria Askmyr; Henrik Lilljebjörn; Marianne Rissler; Christine Karlsson; Stefan Scheding; Johan Richter; Connie J. Eaves; Ravi Bhatia; Marcus Järås; Thoas Fioretos
• Department/s: LUCC: Lund University Cancer Centre; Translational Genomic and Functional Studies of Leukemia; Division of Molecular Hematology (DMH); Stem Cell Center; Division of Clinical Genetics; StemTherapy: National Initiative on Stem Cells for Regenerative Therapy; Bone marrow stem cells and cellular therapies; Targeted therapies in leukemia
• Publishing year: 2020
• Language: English
• Pages: 2095-2104
• Publication/Series: Haematologica
• Volume: 105
• Issue: 8
• Links: http://dx.doi.org/10.3324/haematol.2019.220434
• Document type: Journal article
• Publisher: Ferrata Storti Foundation
• Topic: Hematology
• Status: Published
• Research group: Translational Genomic and Functional Studies of Leukemia; Bone marrow stem cells and cellular therapies; Targeted therapies in leukemia
• ISBN/ISSN/Other: ISSN: 0390-6078