Journal article
Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia
- Abstract:
- Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 19.8MB, Terms of use)
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- Publisher copy:
- 10.1111/bjh.19107
Authors
- Publisher:
- Wiley
- Journal:
- British Journal of Haematology More from this journal
- Volume:
- 204
- Issue:
- 1
- Pages:
- 206-220
- Publication date:
- 2023-09-19
- Acceptance date:
- 2023-09-04
- DOI:
- EISSN:
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1365-2141
- ISSN:
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0007-1048
- Language:
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English
- Keywords:
- Pubs id:
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1532793
- Local pid:
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pubs:1532793
- Deposit date:
-
2023-09-21
Terms of use
- Copyright holder:
- de Castro et al.
- Copyright date:
- 2023
- Rights statement:
- © 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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