Acute myeloid leukaemia cells express high levels of androgen receptor but do not depend on androgen signaling for survival

IF 13.4 1区 医学 Q1 HEMATOLOGY
Farideh Miraki-Moud, Linda Ariza-McNaughton, Thinzar KoKo, Jad Othman, Randal Stronge, Johann de Bono, Nigel Russell, Ian Thomas, Amanda Gilkes, Alan Burnett, Leandro Rodrigues Santiago, Fay Cafferty, Leo Taussig, Allan Thornhill, Simon O’Connor, Dominique Bonnet, David C. Taussig
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Abstract

Male sex is associated with worse outcome in acute myeloid leukemia (AML) in many studies. We analyzed the survival of 4281 patients treated with intensive chemotherapy in the AML17 and AML19 trials based on sex. Men had a significantly lower remission rate than women. Men had a higher incidence of adverse cytogenetic features and a lower incidence of the relatively favorable NPM1 mutation. However, male sex was an independent risk factor for survival in multi-variate analysis. We hypothesized that androgen signaling in men could worsen outcomes by protecting AML cells from chemotherapy. We demonstrated high levels of androgen receptor (AR) expression in AML across cytogenetic risk groups. We showed the AR expression was induced by IL-6 signaling in vitro and correlates with poor overall survival. Androgens had no effect on survival of primary AML cells in vitro, nor did they impact gene expression. Androgens did not protect AML cells against chemotherapy either in vitro or in vivo. Similar results were observed with estrogen signaling through estrogen receptor in vitro in AML cells. In conclusion, targeting the androgen pathway may not be a promising clinical strategy and sex hormone signaling in AML cells does not explain the poorer outcomes of men.

Abstract Image

急性髓系白血病细胞表达高水平的雄激素受体,但不依赖于雄激素信号来生存
在许多研究中,男性与急性髓性白血病(AML)预后较差相关。我们根据性别分析了AML17和AML19试验中4281例接受强化化疗的患者的生存率。男性的缓解率明显低于女性。男性的不良细胞遗传学特征发生率较高,而相对有利的NPM1突变发生率较低。然而,在多变量分析中,男性是一个独立的生存危险因素。我们假设男性中的雄激素信号可能通过保护AML细胞免受化疗而恶化预后。我们证实,在细胞遗传学危险组中,AML中雄激素受体(AR)表达水平较高。我们发现AR的表达是由IL-6信号诱导的,并且与较差的总生存率相关。雄激素对体外原代AML细胞的存活没有影响,也不影响基因表达。无论在体内还是体外,雄激素都不能保护AML细胞抵抗化疗。在体外AML细胞中,通过雌激素受体的雌激素信号传导也观察到类似的结果。总之,靶向雄激素途径可能不是一个有希望的临床策略,AML细胞中的性激素信号传导并不能解释男性预后较差的原因。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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