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Simple Summary: Bortezomib-containing chemotherapy did not improve the clinical outcome in the AAML1031 study in terms of overall survival and event-free survival compared to standard chemotherapy. We characterized epigenetically distinct proteomic profiles in a large cohort of pediatric patients that participated in this study using the reverse-phase protein array. We observed in the patient group that received standard therapy that a higher expression of 16 histone-modulating enzymes (HMEs) was an independent variable that predicted higher relapse risk three years after a second induction therapy compared to those with a lower HME protein expression. Also, there was significantly improved overall survival for those with a high HME expression who were treated with the bortezomib-containing chemotherapy, compared to high-HME patients treated without bortezomib. We also demonstrated that patients with a higher expression of HME had more open chromatin surrounding promoter sides compared to those with lower HME protein levels using ATAC-seq. The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%, p = 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%, p = 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy. [ABSTRACT FROM AUTHOR]

Introduction: The biological heterogeneity of acute myeloid leukemia (AML) complicates personalized medicine. Individual prognosis is typically based on the presence of chromosomal and genetic lesions. Nevertheless, these classifications often lack a priori information about response to therapy. Since the protein expression landscape reflects the functional activity state of cells, we hypothesize that analyzing this can be used for the identification of protein activity markers to provide better risk stratification as well as may provide targeted therapeutic guidance in AML. Areas covered: Herein, we review recently new adopted drugs in the treatment for AML and discuss how quantitative proteomic techniques may contribute to better therapeutic selection in AML. Expert commentary: The net functional state of the cell is defined by the activity of protein within all the pathways that are active in the cell. Recognition of the proteomic profile of the leukemic blast could, therefore, complement current classification systems by providing a better a priori description of what pathways are important within a cell as a guide to the selection of therapy for the patient. [ABSTRACT FROM AUTHOR]