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


  • S. Oberbeck
  • A. Schrader
  • K. Warner
  • D. Jungherz
  • G. Crispatzu
  • J. von Jan
  • M. Chmielewski
  • A. Ianevski
  • H.H. Diebner
  • P. Mayer
  • A. Kondo Ados
  • L. Wahnschaffe
  • T. Braun
  • T.A. Müller
  • P. Wagle
  • A. Bouska
  • T. Neumann
  • S. Pützer
  • L. Varghese
  • N. Pflug
  • M. Thelen
  • J. Makalowski
  • N. Riet
  • H.J.M Göx
  • G. Rappl
  • J. Altmüller
  • M. Kotrová
  • T. Persigehl
  • G. Hopfinger
  • M.L. Hansmann
  • H. Schlößer
  • S. Stilgenbauer
  • J. Dürig
  • D. Mougiakakos
  • M. von Bergwelt-Baildon
  • I. Roeder
  • S. Hartmann
  • M. Hallek
  • R. Moriggl
  • M. Brüggemann
  • T. Aittokallio
  • J. Iqbal
  • S. Newrzela
  • H. Abken
  • M. Herling


  • Blood


  • Blood 136 (24): 2786-2802


  • 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 postthymic T cells. We assessed 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 noncanonical 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 (eg, 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 the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-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 chimeric antigen receptors, these Lck(pr)-hTCL1A(tg) 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 the accumulation of death-resistant memory-type cells that use 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.