Noncanonical effector functions of the T-memory–like T-PLL cell are shaped by cooperative TCL1A and TCR signaling

Abstract

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell-leukemia-1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular post-thymic T-cells. We assessed here activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent non-canonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR-clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR-coreceptors (e.g. CTLA4). TCR-stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T-cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to T-PLL's marked resistance to activation- and FAS-induced cell death. Enforced TCL1A enhanced phosho-activation of TCR-kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or CARs, these Lckpr-hTCL1Atg T-cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR-signals and drives accumulation of death-resistant memory-type cells that utilize amplified low-level stimulatory input and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR- and survival signaling.

Venetoclax treatment of patients with relapsed T-cell prolymphocytic leukemia

“…Ibrutinib and venetoclax are a pairing which has shown synergy in some 9 , but not all 6 , laboratory investigations with T-PLL samples and with reported tolerability in patients with CLL 17 . Two clinical responses 9 and a period of stable disease halting exponential proliferation in another case 10 have been reported also, and a clinical trial (NCT03873493) is underway to further evaluate this combination in patients with T-PLL. Utilizing a multiagent regimen targeting key pathways in T-PLL, a remarkable response with venetoclax plus alemtuzumab, cladribine, and vorinostat was described in a patient with very active disease and who previously had progressed during venetoclax monotherapy ramp-up 8 .…”

“…Prior studies have reported three patients who achieved partial remission (PR) with venetoclax monotherapy 5,6 and a more durable (10 months) complete response with combination venetoclax and pentostatin 7 . Recently, additional case reports have also suggested superior responses when venetoclax was administered in a combination approach [8][9][10] . Herein, we report outcomes of patients with relapsed/refractory T-PLL treated with venetoclax at our institution.…”

The Modes of Dysregulation of the Proto-Oncogene T-Cell Leukemia/Lymphoma 1A

“…The expression of TCL1A in embryonic tissues, as well as its recurrent overexpression and prognostic/predictive value in different malignancies, implicates an important function of TCL1A in key signaling pathways mediating stemness and survival (Figure 1). [24,26,61]; (E) interaction of the TCL1A homodimer with AKT molecules leads to augmented trans-phosphorylation and catalytic activity of the oncogenic Ser/Thr kinase AKT, resulting in increased survival signaling [62]; (F) the interaction of TCL1A with AP-1 components-namely, JUN, JUNB, and FOS, leads to impaired AP-1 signaling and thereby sustained anti-apoptotic signals [11]; (G) TCL1A interacts with IκB and mediates its phosphorylation via ATM, leading to its subsequent ubiquitination-dependent degradation. Inhibition of this negative regulator IκB causes increased NF-κB signaling, which is additionally strengthened by the TCL1A-p300 interaction [11]; (H) physical interaction of TCL1A with DNMT3A reduces the methyltransferase activity of DNMT3A, which leads to a higher number of hypomethylated genomic regions [63], which is implicated in the pathogenesis of CLL [64].…”

“…In Tcl1a −/− mice, the bulge cells show reduced expression of the stem cell marker CD34. Furthermore, a Tcl1a knockout led to reduced proliferation of TA cells, needed for new hair formation[59]; (C) upregulation of Tcl1a leads to metabolic shifts toward aerobic glycolysis via activation of Akt and repression of Pnpt1, thereby contributing to pluripotency of induced pluripotent stem cells (iPSCs)[60]; (D) in cells of chronic lymphocytic leukemia (CLL) and T-cell prolymphocytic leukemia (T-PLL), TCL1A increases the responsiveness to B-cell receptor (BCR) and T-cell receptor (TCR) stimulation, respectively, by a kinase activating effect[24,26,61]; (E) interaction of the TCL1A homodimer with AKT molecules leads to augmented trans-phosphorylation and catalytic activity of the oncogenic Ser/Thr kinase AKT, resulting in increased survival signaling[62]; (F) the interaction of TCL1A with AP-1 components-namely, JUN, JUNB, and FOS, leads to impaired AP-1 signaling and thereby sustained anti-apoptotic signals[11]; (G) TCL1A interacts with IκB and mediates its phosphorylation via ATM, leading to its subsequent ubiquitination-dependent degradation. Inhibition of this negative regulator IκB causes increased NF-κB signaling, which is additionally strengthened by the TCL1A-p300 interaction[11]; (H) physical interaction of TCL1A with DNMT3A reduces the methyltransferase activity of DNMT3A, which leads to a higher number of hypomethylated genomic regions[63], which is implicated in the pathogenesis of CLL[64].…”

Rationale for the combination of venetoclax and ibrutinib in T-prolymphocytic leukemia

“…reported disease stabilization after short-term treatment of one patient with venetoclax plus ibrutinib, but progression after cessation of treatment. 14 Alfayez et al . treated one patient with venetoclax plus pentostatin who achieved complete remission for 10 months.…”