急性髓系白血病的蛋白质基因组亚型

The proteogenomic subtypes of acute myeloid leukemia.

作者信息

Jayavelu Ashok Kumar, Wolf Sebastian, Buettner Florian, Alexe Gabriela, Häupl Björn, Comoglio Federico, Schneider Constanze, Doebele Carmen, Fuhrmann Dominik C, Wagner Sebastian, Donato Elisa, Andresen Carolin, Wilke Anne C, Zindel Alena, Jahn Dominique, Splettstoesser Bianca, Plessmann Uwe, Münch Silvia, Abou-El-Ardat Khali, Makowka Philipp, Acker Fabian, Enssle Julius C, Cremer Anjali, Schnütgen Frank, Kurrle Nina, Chapuy Björn, Löber Jens, Hartmann Sylvia, Wild Peter J, Wittig Ilka, Hübschmann Daniel, Kaderali Lars, Cox Jürgen, Brüne Bernhard, Röllig Christoph, Thiede Christian, Steffen Björn, Bornhäuser Martin, Trumpp Andreas, Urlaub Henning, Stegmaier Kimberly, Serve Hubert, Mann Matthias, Oellerich Thomas

机构信息

Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany; Clinical Cooperation Unit Pediatric Leukemia, DKFZ and Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany; Hopp Children's Cancer Center Heidelberg - KiTZ, Heidelberg, Germany.

Department of Medicine II, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany.

出版信息

Cancer Cell. 2022 Mar 14;40(3):301-317.e12. doi: 10.1016/j.ccell.2022.02.006. Epub 2022 Mar 3.

DOI:10.1016/j.ccell.2022.02.006

PMID:35245447

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis includes cytogenetic profiling and DNA/RNA sequencing. We identify five proteomic AML subtypes, each reflecting specific biological features spanning genomic boundaries. Two of these proteomic subtypes correlate with patient outcome, but none is exclusively associated with specific genomic aberrations. Remarkably, one subtype (Mito-AML), which is captured only in the proteome, is characterized by high expression of mitochondrial proteins and confers poor outcome, with reduced remission rate and shorter overall survival on treatment with intensive induction chemotherapy. Functional analyses reveal that Mito-AML is metabolically wired toward stronger complex I-dependent respiration and is more responsive to treatment with the BCL2 inhibitor venetoclax.

摘要

急性髓系白血病（AML）是一种侵袭性血液癌症，预后较差。我们报告了对252例接受统一治疗的AML患者的骨髓活检进行的全面蛋白质基因组分析，以阐明AML的分子病理生理学，为未来的诊断和治疗方法提供依据。除了深入的定量蛋白质组学外，我们的分析还包括细胞遗传学分析和DNA/RNA测序。我们鉴定出五种蛋白质组学AML亚型，每种亚型都反映了跨越基因组边界的特定生物学特征。其中两种蛋白质组学亚型与患者预后相关，但没有一种与特定的基因组畸变完全相关。值得注意的是，一种仅在蛋白质组中被发现的亚型（线粒体AML），其特征是线粒体蛋白高表达，预后较差，强化诱导化疗治疗时缓解率降低，总生存期缩短。功能分析表明，线粒体AML在代谢上倾向于更强的依赖复合体I的呼吸作用，并且对BCL2抑制剂维奈克拉治疗更敏感。