Evolution of transcriptomic profiles in relapsed inv(16) acute myeloid leukemia

IF 2.1 4区 医学 Q3 HEMATOLOGY
Serena Travaglini , Giorgia Silvestrini , Enrico Attardi , Maurizio Fanciulli , Stefano Scalera , Silvia Antonelli , Luca Maurillo , Raffaele Palmieri , Mariadomenica Divona , Ludovica Ciuffreda , Arianna Savi , Giovangiacinto Paterno , Tiziana Ottone , Caterina Barbieri , Jaroslaw P. Maciejewski , Carmelo Gurnari , Gennaro Ciliberto , Maria Teresa Voso
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Abstract

Acute myeloid leukemia (AML) with inv(16) is typically associated with a favourable prognosis. However, up to 40 % of patients will eventually experience disease relapse. Herein, we dissected the genomic and transcriptomic profile of inv(16) AML to identify potential prognostic markers and therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not differ significantly between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic(n=7) and relapse(n=6) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on an inv(16) cell-line ME-1, but there was no additional advantage in terms of cell death over Azacitidine alone. To enhance Venetoclax efficacy, we tested in vitro effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusions, we identified a downregulated expression of oxidative phosphorylation (OXPHOS) at relapse in AML with inv(16), and explored the in vitro effects of metformin as a potential drug to enhance chemosensitivity in this setting.

复发 inv(16) 急性髓性白血病转录组特征的演变。
患有inv(16)的急性髓性白血病(AML)通常预后良好。然而,高达 40% 的患者最终会复发。在此,我们剖析了inv(16) AML的基因组和转录组特征,以确定潜在的预后标志物和治疗弱点。来自 222 份诊断样本(包括 44 例复发/难治性患者)的测序数据显示,中位数存在 1 个与 inv(16) 共同参与白血病发生的额外突变。值得注意的是,除了复发/难治组的突变负荷增加外,初治诱导失败或复发患者在诊断时的突变情况与队列中的其他患者相比没有显著差异。通过对未配对的诊断样本(7 例)和复发样本(6 例)进行 RNA-Seq 分析,发现氧化磷酸化(OXPHOS)是复发时最显著下调的通路之一。考虑到Venetoclax/阿扎胞苷联合疗法可靶向OXPHOS,我们探讨了其对inv(16)细胞系ME-1的生物效应,但与单独使用阿扎胞苷相比,在细胞死亡方面并无额外优势。为了增强 Venetoclax 的疗效,我们测试了二甲双胍的体外效应,它是一种潜在的药物,能够通过抑制线粒体转移来增强 AML 细胞的化疗敏感性。通过用这种组合挑战 ME-1,我们观察到了显著的协同作用,至少与 Venetoclax/Azacitidine 的作用类似。总之,我们发现了inv(16)型急性髓细胞性白血病复发时氧化磷酸化(OXPHOS)表达下调,并探索了二甲双胍作为一种潜在药物在体外的作用,以增强这种情况下的化疗敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Leukemia research
Leukemia research 医学-血液学
CiteScore
4.00
自引率
3.70%
发文量
259
审稿时长
1 months
期刊介绍: Leukemia Research an international journal which brings comprehensive and current information to all health care professionals involved in basic and applied clinical research in hematological malignancies. The editors encourage the submission of articles relevant to hematological malignancies. The Journal scope includes reporting studies of cellular and molecular biology, genetics, immunology, epidemiology, clinical evaluation, and therapy of these diseases.
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