نبذة مختصرة : Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients. ; Peer reviewed
Relation: We thank Maria Lindstroem (Clinical Pathology, Uppsala University Hospital) and BioVis (Department of Immunology, Genetics and Pathology; Uppsala University) for technical support. Patient samples were provided by U-CAN; Clinical Pathology, Uppsala University Hospital (Sweden); Clinical Genetics, Uppsala University Hospital (Sweden); and Nordic Society of Pediatric Hematology and Oncology (NOPHO). The authors would further like to acknowledge support from Clinical Proteomics Mass Spectrometry at Karolinska University Hospital and Science for Life Laboratory for providing assistance in mass spectrometry and data analysis. The computations and data handling were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at SNIC-SENS partially funded by the Swedish Research Council through grant agreement no. 2018-05973. This work was supported by grants to LH from the Knut and Alice Wallenberg Foundation (KAW 2013-0159), The Swedish Research Council (2013-03486), The Swedish Childhood Cancer Foundation (PR2013-0070 and TJ2013-0045), The Swedish Cancer Society (CAN2013/489), and The Kjell and Maerta Beijer Foundation.; Stratmann , S , Vesterlund , M , Umer , H M , Eshtad , S , Skaftason , A , Herlin , M K , Sundstrom , C , Eriksson , A , Hoglund , M , Palle , J , Abrahamsson , J , Jahnukainen , K , Munthe-Kaas , M C , Zeller , B , Tamm , K P , Lindskog , C , Cavelier , L , Lehtio , J & Holmfeldt , L 2023 , ' Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children ' , Leukemia , vol. 37 , no. 3 , pp. 550–559 . https://doi.org/10.1038/s41375-022-01796-7; 172ddab0-fdb2-4d3f-bb9c-999cf8a92cd3; http://hdl.handle.net/10138/356042; 000903999000001
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