Key Points We identify gain-of-function mutations involving IL2RG, JAK1/3, and STAT5B as well as deleterious mutations affecting EZH2, FBXW10, and CHEK2 in T-PLL. Pharmacologic targeting of primary T-PLL cells with the STAT5 inhibitor pimozide leads to apoptosis.

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.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

An important pathogenic event in EpsteinBarr virus (EBV)- IntroductionThe Epstein-Barr virus (EBV) is a ␥-herpesvirus that infects the majority of the world's adult population. In most persons, the virus is carried life-long as an asymptomatic infection where it establishes persistence by latently infecting memory B lymphocytes. However, in a minority of persons, EBV can contribute to the development of one of several B-cell malignancies, including Burkitt lymphoma (BL). 1 In vitro infection of normal B cells with EBV gives rise to lymphoblastoid cell lines (LCLs) in which there is expression of a limited subset of latent virus genes that include the Epstein-Barr nuclear antigens (2, 3A, 3B, 3C, and LP) and the latent membrane proteins (LMP-1, and LMP-2). 2 In contrast, most EBV-associated lymphomas show a more restricted pattern of latency; for example, in the majority of EBV ϩ BL, Epstein-Barr nuclear antigen-1 is the only viral protein expressed. 3,4 As well as maintaining latency in B lymphocytes, the virus can also induce its replicative cycle in these cells. Thus, at any one time, a small proportion of cells in an LCL may spontaneously enter the lytic cycle or be induced to do so by treatment with chemical agents, such as phorbol esters, or by ligation of surface immunoglobulin (Ig). 5 The replicative cycle of EBV is induced by expression of the immediate-early gene, BZLF1, which alone is sufficient to activate downstream lytic genes and complete viral replication in a permissive cell type. 6,7 A number of studies suggest that EBV replicates in terminally differentiated plasma cells. [8][9][10][11][12] These findings are supported by in vitro studies, which show that the BZLF1 promoter is active in memory cells only after they have been differentiated into plasma cells. 12 The intimate association between terminal differentiation and EBV replication in B cells suggests that the switch from latency to the lytic cycle is controlled by factors that normally regulate plasma cell differentiation. We speculated that the absence of such factors could be important in the pathogenesis of EBV-associated lymphomas because virus replication would otherwise result in tumor cell death.We have focused on BLIMP1, a transcription factor encoded by the PRDM1 gene, which orchestrates plasma cell differentiation by repressing genetic programs associated with the germinal center (GC) stages, while at the same time activating those programs associated with plasma cell functions. 13,14 For example, the BLIMP1-mediated silencing of MYC, BCL6, and PAX5 expression has been shown to be required for plasma cell differentiation. [15][16][17][18][19] BLIMP1 also Submitted September 16, 2010; accepted February 21, 2011. Prepublished online as Blood First Edition paper, March 16, 2011; DOI 10.1182 DOI 10. /blood-2010 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Th...