Proteomic and phosphoproteomic landscapes of acute myeloid leukemia

作者：Michael H. Kramer, Qiang Zhang, Robert W. Sprung, Ryan B. Day, Petra Erdmann-Gilmore, Yang Li, Ziheng Xu, Nichole Helton, Daniel Rince George, Yiling Mi, Peter Westervelt, Jacqueline E. Payton, Sai Mukund Ramakrishnan, Christopher A. Miller, Daniel C. Link, John F. DiPersio, Matthew J. Walter, R. Reid Townsend, Timothy James Ley · 发表于：Blood · 年份：2022 · DOI：10.1182/blood.2022016033 · 被引用次数：134 · 研究领域：Acute Myeloid Leukemia Research、Advanced Proteomics Techniques and Applications、Molecular Biology Techniques and Applications

We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow-derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine k...