American Society of Hematology

Figure 7.

$Clinical associations and a model of T-PLL evolution. (A-C) OS from diagnosis (log-rank tests) of uniformly treated T-PLL patients. See supplemental Figure 10 for associations of T-cell differentiation phenotypes with activation scores and with CD95. (A) The rare composite (n = 5) and naïve (n = 6) T-cell phenotypes were associated with a worse and better outcome than the bulk of CD45RO+ T-PLL, respectively. (B) Correlation of higher cellular activation in 53 T-PLL patients with shorter OS. Analyte cutoffs and definition of the activation score are outlined in the legend of Figure 2A. (C) Differential prognosis of T-PLL patients (n = 73) stratified by TCL1A protein expression (percentage of positive cells in PB; flow cytometry). (D) A T-PLL patient in disease progression under cyclophosphamide (previously refractory to alemtuzumab, bendamustine, and fludarabine) was treated with Venetoclax (800 mg/d) and Ibrutinib (420 mg/d). This treatment stabilized PB lymphocyte counts over the entire period of exposure (middle panel). Blood sampling at the indicated (color-coded) time points reveals the cytotoxic effect of this treatment (PARP cleavage, western blots, lower panel) fitting the synergistic in vitro relationship of both substances from samples before this treatment (top). (E) Proposed model of the proleukemogenic cooperation of TCL1A with TCR signaling. TCL1A is normally silenced upon progression of double negative (DN) to double positive (DP) thymocytes. Physiologically (TCL1A negative peripheral T cell, left box), activation via the matured TCR is regulated by coreceptors and only high avidity antigens mediate TCR signals and cell activation. In the T-PLL precursor, genetic aberrations dictate deregulated expression of the antiapoptotic proto-oncogenes TCL1A or MTCP1 (t(X;14)). The resulting survival benefit is supported by the effect of additional genomic alterations (eg, ATM). TCL1A enhances p-kinase responses (underlying physical interactions described in Herling et al10) and cellular effector functions such as IL-2 secretion (right box) of the affected T cell and contributes to its resistance to safeguarding cell death (AICD). By enhancing TCR signals, TCL1A enables low-avidity (auto)antigens to trigger a beneficial T-cell activation, in an MHC-dependent context or in autonomous TCR activation. By lowering the TCR-signaling threshold (sensitizer effect), TCL1A propels the transition of naïve T cells into an expanding memory T-cell pool as the origin of final T-PLL outgrowth (see also TCL1A-tg mice). Sustained activation (increased autonomy) is further mediated by impaired control mechanisms (eg, CTLA4 downregulation).$

Clinical associations and a model of T-PLL evolution. (A-C) OS from diagnosis (log-rank tests) of uniformly treated T-PLL patients. See supplemental Figure 10 for associations of T-cell differentiation phenotypes with activation scores and with CD95. (A) The rare composite (n = 5) and naïve (n = 6) T-cell phenotypes were associated with a worse and better outcome than the bulk of CD45RO⁺ T-PLL, respectively. (B) Correlation of higher cellular activation in 53 T-PLL patients with shorter OS. Analyte cutoffs and definition of the activation score are outlined in the legend of Figure 2A. (C) Differential prognosis of T-PLL patients (n = 73) stratified by TCL1A protein expression (percentage of positive cells in PB; flow cytometry). (D) A T-PLL patient in disease progression under cyclophosphamide (previously refractory to alemtuzumab, bendamustine, and fludarabine) was treated with Venetoclax (800 mg/d) and Ibrutinib (420 mg/d). This treatment stabilized PB lymphocyte counts over the entire period of exposure (middle panel). Blood sampling at the indicated (color-coded) time points reveals the cytotoxic effect of this treatment (PARP cleavage, western blots, lower panel) fitting the synergistic in vitro relationship of both substances from samples before this treatment (top). (E) Proposed model of the proleukemogenic cooperation of TCL1A with TCR signaling. TCL1A is normally silenced upon progression of double negative (DN) to double positive (DP) thymocytes. Physiologically (TCL1A negative peripheral T cell, left box), activation via the matured TCR is regulated by coreceptors and only high avidity antigens mediate TCR signals and cell activation. In the T-PLL precursor, genetic aberrations dictate deregulated expression of the antiapoptotic proto-oncogenes TCL1A or MTCP1 (t(X;14)). The resulting survival benefit is supported by the effect of additional genomic alterations (eg, ATM). TCL1A enhances p-kinase responses (underlying physical interactions described in Herling et al¹⁰) and cellular effector functions such as IL-2 secretion (right box) of the affected T cell and contributes to its resistance to safeguarding cell death (AICD). By enhancing TCR signals, TCL1A enables low-avidity (auto)antigens to trigger a beneficial T-cell activation, in an MHC-dependent context or in autonomous TCR activation. By lowering the TCR-signaling threshold (sensitizer effect), TCL1A propels the transition of naïve T cells into an expanding memory T-cell pool as the origin of final T-PLL outgrowth (see also TCL1A-tg mice). Sustained activation (increased autonomy) is further mediated by impaired control mechanisms (eg, CTLA4 downregulation).

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