High Mitochondrial Protein Expression as a Potential Predictor of Relapse Risk in Acute Myeloid Leukemia Patients with the Monocytic FAB Subtypes M4 and M5

Simple Summary Proteins serve as the primary regulators of cellular functions, and the development of new drugs largely focuses on target proteins that play crucial roles in specific diseases. Quantitative proteomics has emerged as a promising analytic technique, offering the potential to identify disease-related proteins and develop novel biomarkers linked to prognosis and subclassification of specific cancer types. The aim of this study was to examine the potential of mass spectrometry-based proteomic profiling in identifying distinct protein expression and phosphorylation patterns that may help predict relapse risk in acute myeloid leukemia (AML) patients with different French-American-British (FAB) subtypes. Our approach exposed differential protein expression and regulation of phosphorylated sites among various FAB subtypes. Moreover, the presence of high levels of mitochondrial proteins at diagnosis predicts an unfavorable prognosis with a high relapse rate for patients who exhibit the FAB M4/M5 subtype.Abstract AML is a highly aggressive and heterogeneous form of hematological cancer. Proteomics-based stratification of patients into more refined subgroups may contribute to a more precise characterization of the patient-derived AML cells. Here, we reanalyzed liquid chromatography-tandem mass spectrometry (LC-MS/MS) generated proteomic and phosphoproteomic data from 26 FAB-M4/M5 patients. The patients achieved complete hematological remission after induction therapy. Twelve of them later developed chemoresistant relapse (RELAPSE), and 14 patients were relapse-free (REL_FREE) long-term survivors. We considered not only the RELAPSE and REL_FREE characteristics but also integrated the French-American-British (FAB) classification, along with considering the presence of nucleophosmin 1 (NPM1) mutation and cytogenetically normal AML. We found a significant number of differentially enriched proteins (911) and phosphoproteins (257) between the various FAB subtypes in RELAPSE patients. Patients with the myeloblastic M1/M2 subtype showed higher levels of RNA processing-related routes and lower levels of signaling related to terms like translation and degranulation when compared with the M4/M5 subtype. Moreover, we found that a high abundance of proteins associated with mitochondrial translation and oxidative phosphorylation, particularly observed in the RELAPSE M4/M5 NPM1 mutated subgroup, distinguishes relapsing from non-relapsing AML patient cells with the FAB subtype M4/M5. Thus, the discovery of subtype-specific biomarkers through proteomic profiling may complement the existing classification system for AML and potentially aid in selecting personalized treatment strategies for individual patients.