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

von Palffy, Sofia LU ; Landberg, Niklas LU orcid ; Sandén, Carl LU ; Zacharaki, Dimitra LU ; Shah, Mansi ; Nakamichi, Naoto ; Hansen, Nils LU ; Askmyr, Maria LU ; Lilljebjörn, Henrik LU orcid and Rissler, Marianne LU , et al. (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.

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organization
publishing date
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
2024-05-29 18:50:22
@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}},
}