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Inhibition of RhoA-mediated secretory autophagy in megakaryocytes mitigates myelofibrosis in mice.

Authors :
Becker IC
Barrachina MN
Lykins J
Camacho V
Stone AP
Chua BA
Signer RAJ
Machlus KR
Whiteheart SW
Roweth HG
Italiano JE
Source :
BioRxiv : the preprint server for biology [bioRxiv] 2024 Dec 05. Date of Electronic Publication: 2024 Dec 05.
Publication Year :
2024

Abstract

Megakaryocytes (MKs) are large, polyploid cells that contribute to bone marrow homeostasis through the secretion of cytokines such as transforming growth factor β1 (TGFβ1). During neoplastic transformation, immature MKs accumulate in the bone marrow where they induce fibrotic remodeling ultimately resulting in myelofibrosis. Current treatment strategies aim to prevent MK hyperproliferation, however, little is understood about the potential of targeting dysregulated cytokine secretion from neoplastic MKs as a novel therapeutic avenue. Unconventional secretion of TGFβ1 as well as interleukin 1β (IL1β) via secretory autophagy occurs in cells other than MKs, which prompted us to investigate whether similar mechanisms are utilized by MKs. Here, we identified that TGFβ1 strongly co-localized with the autophagy marker light chain 3B in native MKs. Disrupting secretory autophagy by inhibiting the small GTPase RhoA or its downstream effector Rho kinase (ROCK) markedly reduced TGFβ1 and IL1β secretion in vitro . In vivo , conditional deletion of the essential autophagy gene Atg5 from the hematopoietic system limited megakaryocytosis and aberrant cytokine secretion in an MPL <superscript>W515L</superscript> -driven transplant model. Similarly, mice with a selective deletion of Rhoa from the MK and platelet lineage were protected from progressive fibrosis. Finally, disease hallmarks in MPL <superscript>W515L</superscript> -transplanted mice were attenuated upon treatment with the autophagy inhibitor hydroxychloroquine or the ROCK inhibitor Y27632, either as monotherapy or in combination with the JAK2 inhibitor ruxolitinib. Overall, our data indicate that aberrant cytokine secretion is dependent on secretory autophagy downstream of RhoA, targeting of which represents a novel therapeutic avenue in the treatment of myelofibrosis.<br />One Sentence Summary: TGFβ1 is released from megakaryocytes via RhoA-mediated secretory autophagy, and targeting this process can alleviate fibrosis progression in a preclinical mouse model of myelofibrosis.

Details

Language :
English
ISSN :
2692-8205
Database :
MEDLINE
Journal :
BioRxiv : the preprint server for biology
Publication Type :
Academic Journal
Accession number :
39677616
Full Text :
https://doi.org/10.1101/2024.12.04.626665