Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.

Autor: de Castro FA; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil., Mehdipour P; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK., Chakravarthy A; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Ettayebi I; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Loo Yau H; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Medina TS; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Translational Immuno-Oncology Group, International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil., Marhon SA; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., de Almeida FC; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.; Instituto de Investigação em Imunologia, Institutos Nacionais de Ciência e Tecnologia (INCT-iii), Salvador, Brazil., Bianco TM; Hematology Division, Department of Medical Imaging, Hematology and Clinical Oncology, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Arruda AGF; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Devlin R; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., de Figueiredo-Pontes LL; Hematology Division, Department of Medical Imaging, Hematology and Clinical Oncology, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Chahud F; Department of Pathology and Forensic Medicine, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., da Costa Cacemiro M; Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil., Minden MD; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Gupta V; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., De Carvalho DD; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2024 Jan; Vol. 204 (1), pp. 206-220. Date of Electronic Publication: 2023 Sep 19.
DOI: 10.1111/bjh.19107
Abstrakt: 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.
(© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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