A high-content cytokine screen identifies myostatin propeptide as a positive regulator of primitive chronic myeloid leukemia cells
(2020) In Haematologica 105(8). p.2095-2104- 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 primitive 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 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... (More)
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+ 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 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.
(Less)
- author
- organization
-
- LUCC: Lund University Cancer Centre
- Translational Genomic and Functional Studies of Leukemia (research group)
- 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 (research group)
- Targeted therapies in leukemia (research group)
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Haematologica
- volume
- 105
- issue
- 8
- pages
- 10 pages
- publisher
- Ferrata Storti Foundation
- external identifiers
-
- scopus:85089126622
- pmid:31582541
- ISSN
- 0390-6078
- DOI
- 10.3324/haematol.2019.220434
- language
- English
- LU publication?
- yes
- id
- 74898939-f836-4c14-b17d-56d62bf02db2
- date added to LUP
- 2020-08-18 08:36:56
- date last changed
- 2024-10-03 07:30:08
@article{74898939-f836-4c14-b17d-56d62bf02db2, abstract = {{<p>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<sup>+</sup> CD38<sup>low</sup> 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.</p>}}, author = {{von Palffy, Sofia and Landberg, Niklas and Sandén, Carl and Zacharaki, Dimitra and Shah, Mansi and Nakamichi, Naoto and Hansen, Nils and Askmyr, Maria and Lilljebjörn, Henrik and Rissler, Marianne and Karlsson, Christine and Scheding, Stefan and Richter, Johan and Eaves, Connie J. and Bhatia, Ravi and Järås, Marcus and Fioretos, Thoas}}, issn = {{0390-6078}}, language = {{eng}}, number = {{8}}, pages = {{2095--2104}}, publisher = {{Ferrata Storti Foundation}}, series = {{Haematologica}}, title = {{A high-content cytokine screen identifies myostatin propeptide as a positive regulator of primitive chronic myeloid leukemia cells}}, url = {{http://dx.doi.org/10.3324/haematol.2019.220434}}, doi = {{10.3324/haematol.2019.220434}}, volume = {{105}}, year = {{2020}}, }