T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

Introduction: T-cell prolymphocytic leukemia (T-PLL) is a very rare & aggressive disease. Therapeutic advances during recent years have been very limited. Even after initial response, the vast majority of T-PLL patients (pts) relapse quickly and the median overall survival remains below 2 years (ys). This also holds true for induction therapies with the anti-CD52 antibody Alemtuzumab (A). Furthermore, life-threatening viral infections are a severe problem in pts treated with this antibody. In a precursor trial (Hopfinger et al, Cancer 2013), we evaluated a consolidation therapy with A after polychemotherapy induction.

BACKGROUND Scarce systematic trial data have prevented uniform therapeutic guidelines for T‐cell prolymphocytic leukemia (T‐PLL). A central need in this historically refractory tumor is the controlled evaluation of multiagent chemotherapy and its combination with the currently most active single agent, alemtuzumab. METHODS This prospective multicenter phase 2 trial assessed response, survival, and toxicity of a novel regimen in previously treated (n = 9) and treatment‐naive (n = 16) patients with T‐PLL. Induction by fludarabine, mitoxantrone, and cyclophosphamide (FMC), for up to 4 cycles, was followed by alemtuzumab (A) consolidation, up to 12 weeks. RESULTS Of the 25 patients treated with FMC, 21 subsequently received alemtuzumab. Overall response rate to FMC was 68%, comprising 6 complete remissions (all bone‐marrow confirmed) and 11 partial remissions. Alemtuzumab consolidation increased the intent‐to‐treat overall response rate to 92% (12 complete remissions; 11 partial remissions). Median overall survival after FMC‐A was 17.1 months and median progression‐free survival was 11.9 months. Progression‐free survival tended to be shorter for patients with high‐level T‐cell leukemia 1 oncoprotein expression. Hematologic toxicities were the most frequent grade 3/4 side effects under FMC‐A. Exclusively in the 21 alemtuzumab‐consolidated patients, 13 cytomegalovirus reactivations were observed; 9 of these 13 represented a clinically relevant infection. CONCLUSIONS FMC‐A is a safe and efficient protocol in T‐PLL, which compares favorably to published data. Cancer 2013;119:2258–2267. © 2013 American Cancer Society.

Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.

T-cell receptor (TCR) signaling is pivotal in T-cell development and function. In peripheral T-cell lymphomas/leukemias (PTCL/L), histogenesis, transforming events, epidemiology, and clinical presentation are also closely linked to TCR-mediated influences. After reviewing the physiology of normal TCR signaling and cellular responses, we describe here the association of subgroups of PTCL/L with specific patterns of TCR activation as relevant tumor-initiating and/or tumor-sustaining programs. We identify PTCL/L with a functionally intact TCR machinery in which stimulation is possibly incited by exogenous antigens or autoantigens. Distinct from these are tumors with autonomous oncogenic signaling by dysregulated TCR components uncoupled from extrinsic receptor input. A further subset is characterized by transforming events that activate molecules acting as substitutes for TCR signaling, but triggering similar downstream cascades. We finally discuss the consequences of such a functional model for TCR-targeted therapeutic strategies including those that are being tested in the clinic and those that still require further development.

Mature T-cell lymphomas/leukemias (MTCL) have been understudied lymphoid neoplasms that currently receive growing attention. Our historically rudimentary molecular understanding and dissatisfactory interventional success in this complex and for the most part poor-prognostic group of tumors is only slightly improving. A major limiting aspect in further progress in these rare neoplasms is the lack of suitable model systems that would substantially facilitate pathogenic studies and pre-clinical drug evaluations. Such representations of MTCL have thus far not been systematically appraised. We therefore provide an overview on existing models and point out their particular advantages and limitations in the context of the specific scientific questions. After addressing issues of species-specific differences and classifications, we summarize data on MTCL cell lines of human as well as murine origin, on murine strain predispositions to MTCL, on available models of genetically engineered mice, and on transplant systems. From an in-silico meta-analysis of available primary data of gene expression profiles on human MTCL we cross-reference genes reported to transform T-cells in mice and reflect on their general vs entity-restricted relevance and on target-promoter influences. Overall, we identify the urgent need for new models of higher fidelity to human MTCL with respect to their increasingly recognized diversity and to predictions of drug response.

Signal transduction to nuclear factor-kappa B (NF-κB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regulator of NF-κB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-κB kinase (IKK) complex and the phosphatase PP4c, thereby directing PP4c activity to dephosphorylate and inactivate the IKK complex. PP4R1 expression was triggered upon activation and proliferation of primary human T lymphocytes and deficiency for PP4R1 caused sustained and increased IKK activity, T cell hyperactivation, and aberrant NF-κB signaling in NF-κB-addicted T cell lymphomas. Collectively, our results unravel PP4R1 as a previously unknown activation-associated negative regulator of IKK activity in lymphocytes whose downregulation promotes oncogenic NF-κB signaling in a subgroup of T cell lymphomas.

Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of lymphatic neoplasms, which originate from mature (post-thymic) T-cells. Although comprising less than 15% of all non-Hodgkin lymphomas (NHL) in adults in Western countries, T-cell lymphomas still pose a considerable clinical challenge. To date, no standard therapy is available for the treatment of these T-cell malignancies. Treatment options that brought about substantial clinical progress in B-cell lymphomas perform only very poorly when used for T-cell lymphomas. With standard chemotherapy such as CHOP approximately 30% of T-cell lymphomas show a primary refractory course and only 35% of patients survive after 3–5 years. Therefore, novel treatment approaches need to be designed and validated in clinical trials. Here we discuss recent data including those presented at the last annual meeting of the American Society of Haematology (ASH 2009). Currently under investigation are new treatment modalities such as immune modulatory drugs, antifolates or histone deacetylase inhibitors. In addition, we present the ongoing trials that incorporate these new modalities.

Although activation of the B-cell receptor (BCR) signaling pathway is implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. T-cell leukemia 1 (TCL1), the AKT modulator and proto-oncogene, is differentially expressed in CLL and linked to its pathogenesis based on CD5(+) B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR stimulation in 70 CLL cases. The growth kinetics after BCR engagement correlated strongly with the degree and timing of induced AKT phospho-activation. This signaling intensity was best predicted by TCL1 levels and the kinetics of TCL1-AKT corecruitment to BCR membrane activation complexes, which further included the kinases LYN, SYK, ZAP70, and PKC. High TCL1 levels were also strongly associated with aggressive disease features, such as advanced clinical stage, higher white blood cell counts, and shorter lymphocyte doubling time. Higher TCL1 levels independently predicted an inferior clinical outcome (ie, shorter progression-free survival, P < .001), regardless of therapy regimen, especially for ZAP70(+) tumors. We propose TCL1 as a marker of the BCR-responsive CLL subset identifying poor prognostic cases where targeting BCR-associated kinases may be therapeutically useful.