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Epigenetic modifications are dynamic and reversible, making them attractive targets for therapeutic intervention in cancer. Although several drugs targeting epigenetic modifications (epidrugs) have been clinically approved, their application in T-cell acute lymphoblastic leukemia (T-ALL) remains limited, and predictive biomarkers of response are lacking. Here, we present a mass spectrometry (MS)-based pharmacoepigenetic approach to profile histone post-translational modifications (hPTMs) to identify signatures associated with drug sensitivity in T-ALL . Baseline hPTM landscapes were previously established by our group for 21 T-ALL cell lines using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Here, we treated these cell lines with a panel of nine drugs including histone deacetylase inhibitors and DNA methyltransferase inhibitors (epidrugs), alongside anthracyclines, which were included due to their known chromatin-related effects. Correlation of cell viability data with hPTM levels revealed distinct hPTM signatures linked to sensitivity for each drug class. These signatures were subsequently evaluated in T-ALL patient-derived xenograft (PDX) models. However, our analysis revealed substantial discrepancies in hPTM sensitivity signatures compared to those observed in vitro. Co-variation network analysis highlighted divergence in hPTM-hPTM correlation between the two models, underscoring limitations of cell lines for modeling dynamic epigenetic regulation in vivo. Our findings establish a framework for MS-based hPTM profiling in T-ALL and emphasize the importance of model selection in developing predictive epigenetic biomarkers.