期刊
BLOOD
卷 136, 期 24, 页码 2786-2802出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019003348
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资金
- Regional Computing Center of the University of Cologne
- DFG as part of the collaborative research group on mature T-cell lymphomas, CONTROL-T [FOR1961, HE3553/4-2, RO3500/4-2]
- EU Transcan-2 consortium ERANET-PLL
- ERAPerMed consortium JAKSTAT-TARGET
- Koln Fortune Program
- Fritz Thyssen Foundation [10.15.2.034MN]
- Jose Carreras Leukemia Foundation [DJCLS 03 F/2016]
- DFG Sequencing Costs in Projects Grant [SCHR1668/1-1]
- Academy of Finland [292611, 279163, 295504, 310507, 326238]
- European Union's Horizon 2020 Research and Innovation Program (ERA PerMed JAKSTAT-TARGET)
- Cancer Society of Finland
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 activationand 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 Lckpr-hTCL1AtgT 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.
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