干细胞特性与干扰素信号通路比例作为骨髓增生性肿瘤进展为急性髓系白血病的生物标志物和治疗靶点。
Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.
发表日期：2023 Sep 19
作者：
Fabíola Attié de Castro, Parinaz Mehdipour, Ankur Chakravarthy, Ilias Ettayebi, Helen Loo Yau, Tiago Silva Medina, Sajid A Marhon, Felipe Campos de Almeida, Thiago Mantello Bianco, Andrea G F Arruda, Rebecca Devlin, Lorena Lobo de Figueiredo-Pontes, Fernando Chahud, Maira da Costa Cacemiro, Mark D Minden, Vikas Gupta, Daniel D De Carvalho
来源：
BRITISH JOURNAL OF HAEMATOLOGY
摘要：
在骨髓增殖性肿瘤（MPN）的管理中，转化为侵袭性二次急性髓系白血病（sAML）是一个重大挑战。由于MPN的病理生理与干扰素（IFN）信号通路的活化以及AML的发生和侵袭性均与白血病干细胞（LSCs）相关，因此我们研究了MPN到sAML进展中的这些信号通路。我们发现高IFN信号与MPN和AML样本中的低LSC信号相关，而MPN进展和AML转化表现为IFN信号的降低和LSC标志物的增加。MPN患者中LSC与IFN表达比例高与临床不良预后和更高的克隆形成潜能相关。此外，低甲基化剂（HMAs）的治疗通过诱导病毒模拟反应来激活MPN细胞中的IFN信号通路。这一反应以双链RNA（dsRNA）形成和MDA5/RIG-I的激活为特征。HMA诱导的IFN反应导致LSC标志物的减少，从而降低了干性。这些发现揭示了MPN到sAML进展中病毒模拟的常见逃避，将LSC与IFN表达比率确定为进展生物标志物，并表明HMAs治疗可以通过重新激活dsRNA相关的IFN信号在小鼠模型中导致造血反应。© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
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.