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Myostatin propeptide expands primitive CML cells
stimulation with TGF-b1, we found SMAD2/3 phospho- rylation as well as reduced growth and survival of pri- mary CD34+ CML cells. This suggests that MSTNpp- induced SMAD2/3 activation is an unlikely cause of the growth-promoting effects. Instead, the increased STAT5 phosphorylation is a probable mechanism by which MSTNpp expands primitive CML cells. Although STAT5 phosphorylation was high in the unstimulated control cells (consistent with STAT5 being a well-known media- tor and downstream target of the BCR-ABL1 fusion in CML)2,42 MSTNpp stimulation further activated STAT5. However, cross-talk between STAT5, TGF-b family sig- naling members and other signaling pathways might also contribute to the growth-promoting effects of MSTNpp in primitive CML cells.
In conclusion, we here identify several novel positive regulators of primitive CML cells using a high-content cytokine screen. We show that the myostatin antagonist MSTNpp binds to the surface of CML cells, induces acti- vation of STAT5 and SMAD2/3, and has a previously unrecognized growth-promoting effect on primitive CML cells and corresponding normal cells. Further studies are needed to investigate whether interfering with MSTNpp
would translate into new therapeutic opportunities in CML.
Acknowledgments
We wish to thank Anna Hammarberg and the Multipark Cellomics Platform, Lund University, Lund, for help with the screening. We also thank Drs. Henrik Hjort-Hansen and Kourosh Lofti and the Nordic CML Study Group for providing clinical samples and patient characteristics.
Funding
This work was supported by the Swedish Cancer Society, the Swedish Children’s Cancer Foundation, the Medical Faculty of Lund University, the Swedish Research Council, the ISREC Foundation by a joint grant to Swiss Cancer Center, Lusanne, CREATE Health Cancer Center, from the Biltema foundation, the Medical Faculty of Lund University and the Knut and Alice Wallenberg Foundation. Grant support was also received from a Terry Fox Foundation New Frontiers Program Project (#1074), a Stem Cell Network of Centres of Excellence grant (#F17/DT2), and grants from the Canadian Cancer Society Research Institute (#704257 and #705047) and the Leukemia & Lymphoma Society of Canada (#417871).
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