Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2023
|
| _version_ | 1826312135323418624 |
|---|---|
| author | de Castro, FA Mehdipour, P Chakravarthy, A Ettayebi, I Loo Yau, H Medina, TS Marhon, SA de Almeida, FC Bianco, TM Arruda, AGF Devlin, R de Figueiredo‐Pontes, LL Chahud, F da Costa Cacemiro, M Minden, MD Gupta, V De Carvalho, DD |
| author_facet | de Castro, FA Mehdipour, P Chakravarthy, A Ettayebi, I Loo Yau, H Medina, TS Marhon, SA de Almeida, FC Bianco, TM Arruda, AGF Devlin, R de Figueiredo‐Pontes, LL Chahud, F da Costa Cacemiro, M Minden, MD Gupta, V De Carvalho, DD |
| author_sort | de Castro, FA |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T08:23:06Z |
| format | Journal article |
| id | oxford-uuid:5b301578-a2ca-4b3f-a243-2d7d41d4a92d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:23:06Z |
| publishDate | 2023 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:5b301578-a2ca-4b3f-a243-2d7d41d4a92d2024-02-08T09:32:47ZRatio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemiaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5b301578-a2ca-4b3f-a243-2d7d41d4a92dEnglishSymplectic ElementsWiley2023de Castro, FAMehdipour, PChakravarthy, AEttayebi, ILoo Yau, HMedina, TSMarhon, SAde Almeida, FCBianco, TMArruda, AGFDevlin, Rde Figueiredo‐Pontes, LLChahud, Fda Costa Cacemiro, MMinden, MDGupta, VDe Carvalho, DDProgression 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. |
| spellingShingle | de Castro, FA Mehdipour, P Chakravarthy, A Ettayebi, I Loo Yau, H Medina, TS Marhon, SA de Almeida, FC Bianco, TM Arruda, AGF Devlin, R de Figueiredo‐Pontes, LL Chahud, F da Costa Cacemiro, M Minden, MD Gupta, V De Carvalho, DD Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia |
| title | Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia |
| title_full | Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia |
| title_fullStr | Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia |
| title_full_unstemmed | Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia |
| title_short | Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia |
| title_sort | ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia |
| work_keys_str_mv | AT decastrofa ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT mehdipourp ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT chakravarthya ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT ettayebii ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT looyauh ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT medinats ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT marhonsa ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT dealmeidafc ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT biancotm ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT arrudaagf ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT devlinr ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT defigueiredopontesll ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT chahudf ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT dacostacacemirom ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT mindenmd ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT guptav ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia AT decarvalhodd ratioofstemnesstointerferonsignallingasabiomarkerandtherapeutictargetofmyeloproliferativeneoplasmprogressiontoacutemyeloidleukaemia |