The cellular hierarchy of acute myeloid leukemia informs personalized treatment

Yannik Severin, Yasmin Festl, Tobias Matthieu Benoit, Rebekka Wegmann, Benjamin D. Hale, Michael Roiss, Anne-Kathrin Kienzler, Thomas Pabst, Michael Scharl, Shinichi Sunagawa, Markus G. Manz, Antonia M.S. Mueller, Berend Snijder
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Abstract

Acute myeloid leukemia (AML) is characterized by malignant myeloid precursors that span a cellular hierarchy from dedifferentiated leukemic stem cells to mature blasts. While the diagnostic and prognostic importance of AML blast maturation is increasingly recognized, personalized therapies are currently not tailored to a patients individual makeup of this cellular hierarchy. In this study, we use multiplexed image-based ex vivo drug screening (pharmacoscopy) to systematically quantify the drug sensitivity across the cellular hierarchy of AML patients. We analyzed 174 prospective and longitudinal patient samples from 44 newly diagnosed AML patients, which indicated that differences in the AML hierarchy significantly identified poor responses to first-line therapy, outperforming European LeukemiaNet (ELN) criteria. Critically, drug response profiling across the AML hierarchy of each patient improved the accuracy of predicting patient response to first-line therapy (AUC 0.91), and revealed alternative individualized treatment options targeting the complete AML hierarchy of non-responding patients. We confirmed these findings in an independent cohort of 26 relapsed/refractory AML patients, for whom pan-hierarchy response profiling improved response predictions post hoc. Overall, our results quantify the clinical importance of therapeutically targeting the complete cellular hierarchy of newly diagnosed AML, and identify multiplexed image-based ex vivo drug screening to enable quantification and targeting of the AML maturation hierarchy for improved personalized treatment.
急性髓性白血病的细胞分级为个性化治疗提供依据
急性髓细胞白血病(AML)的特征是恶性髓细胞前体跨越从去分化白血病干细胞到成熟囊泡的细胞层次结构。虽然人们越来越认识到急性髓细胞白血病囊泡成熟在诊断和预后方面的重要性,但目前还没有根据患者在细胞层次结构中的个体构成量身定制个性化疗法。在这项研究中,我们利用基于多路复用图像的体外药物筛选(药理学)系统地量化了急性髓细胞性白血病患者整个细胞层次的药物敏感性。我们分析了来自 44 名新诊断的急性髓细胞性白血病患者的 174 份前瞻性和纵向患者样本,结果表明急性髓细胞性白血病分层的差异能显著识别对一线治疗的不良反应,优于欧洲白血病网络(ELN)标准。重要的是,对每位患者的急性髓细胞性白血病分层进行药物反应分析提高了预测患者对一线治疗反应的准确性(AUC 0.91),并揭示了针对无反应患者的完整急性髓细胞性白血病分层的其他个体化治疗方案。我们在一个由 26 名复发/难治急性髓细胞白血病患者组成的独立队列中证实了这些研究结果,对这些患者的泛分层反应谱分析提高了事后反应预测的准确性。总之,我们的研究结果量化了针对新诊断的急性髓细胞性白血病的完整细胞层次结构进行治疗的临床重要性,并确定了基于多路复用图像的体外药物筛选,以实现急性髓细胞性白血病成熟层次结构的量化和靶向,从而改善个性化治疗。
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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