Overview and drug response landscape of T-PLL. (A) Schematic overview of the ex vivo drug screens. PBMCs with tumor cells were isolated from patient blood and cultured with drugs for 48 hours ex vivo, before cell viability was measured based on adenosine triphosphate-dependent luminescence. (B) Overview of the patient samples and drug libraries used for screens A through E. (C) Cell viability of 6 patient-derived primary T-PLL samples in screen A. Viabilities are relative to a DMSO negative control after treatment with 2516 drugs averaged over all concentrations (n = 2-6). Drugs were ranked based on their median decrease in cell viability (across all patient samples and concentrations) from most lethal (left) to mostly neutral (right). (D) Dose response curves showing the viability of patient-derived T-PLL samples (n = 25, each line represents a patient) to fludarabine relative to a DMSO negative control. Corresponding dose response for T-PLL samples to nutlin-3a (n = 25) (E) and venetoclax (n = 10) (F). (G) Varying activity of different BH3 mimetics in 9 patient-derived T-PLL samples. Color hues show the log₂-transformed inhibitory constant (K_I) of each compound for the antiapoptotic protein Bcl-2.^13-17 A small K_I indicates high binding affinity between an inhibitory ligand and its receptor. Dose response curves showing the viability of patient-derived T-PLL samples to selinexor (n = 10) (H), bafilomycin A1 (n = 8) (I), and birinapant (n = 8) (J). ATP, adenosine triphosphate; AITL, angioimmunoblastic T-cell lymphoma; AKT, alpha serine/threonine kinase; BCR, B-cell receptor; BRAF, B-Raf proto-oncogene, serine/threonine kinase; DLBCL, diffuse large B-cell lymphoma; EGFR, epidermal growth factor receptor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated extracellular signal-regulated kinase; mTOR, mammalian target of rapamycin; MZL, marginal zone lymphoma; PI3K, phosphoinositide 3-kinase; Prg., programmed; PTCL, peripheral T-cell lymphoma; ROS, reactive oxygen species; TCR, T-cell receptor.