ATL is caused by the HTLV-1 retrovirus but it is unknown how this virus leads to cellular transformation. The only HTLV-1 gene product that is expressed in all ATL cells is HBZ but exactly how HBZ transforms T lymphocytes is unclear. Using genomic scale RNA interference, we identified a regulatory network involving the transcription factors BATF3 and IRF4 that is essential for ATL proliferation and survival. Through the use of available gene expression profiling data, we showed that BATF3/IRF4 downstream targets are a hallmark of ATL that distinguishes it from other T-cell lymphoma subsets. We hypothesize that HBZ might potentiate the regulatory network as its mechanism of action. Indeed, we showed using CRISPR mediated knockdown of HBZ and genomic wide profiling of HBZ binding sites that HBZ transactivates BATF3 and thereby augments the expression of BATF3/IRF-4 target genes. Finally, we showed that the BET protein inhibitor JQ1 extinguishes BATF3 expression providing a means to target the action of the HBZ oncoprotein therapeutically. Indeed, ATL xenografts were significantly retarded in their growth by BET inhibitor treatment. Our preclinical studies provide a solid rationale for the initiation of clinical trials of BET inhibitors in ATL. In additional studies, we demonstrated that disorders of common gamma cytokine receptor JAK/STAT pathway are pervasive in T-cell malignancy. As assessed by pSTAT3/pSTAT5 phosphorylation and nuclear translocation there is a proportion of from rare to 86% of virtually all subsets of T-cell lymphoma that manifest such activation of the pathway. In these T-cell malignancies with an activated JAK/STAT pathway activating mutations of STAT3/STAT5B, JAK1, JAK3 were frequent but not sufficient to initiate proliferation and only augmented signals from the cytokine receptor JAK/STAT pathway. pSTAT malignant T-cell lines were addicted to JAK1 and JAK3 whether or not they were mutated. Even with activating JAK mutations there was a requirement for expression of a functional cytokine receptor that played two roles, first as a scaffold for cross-activation of JAK kinases and second as a docking site for recruitment of STAT transcription factors. These studies support the development of a pure JAK1 or pure JAK3 inhibitor as an element in multidrug therapy of T-cell malignancy. A major focus of the Waldmann/Staudt Laboratory is to define molecular abnormalities of HTLV-1 associated ATL. Previously we demonstrated that HTLV-1 encoded Tax transactivates two autocrine (IL-2/IL-2R, IL-15/IL-15R alpha) and one paracrine (IL-9) pathway. To extend these observations we performed molecular interference Achilles' heel screening of ATL cell lines employing a library of retroviral vectors for inducible expression of short-hairpin RNAs (shRNAs) to identify genes essential for leukemic cell survival. Using this loss-of-function screen, 6 of 7 distinct cytokine-dependent ATL cell lines were shown to be critically dependent on JAK1 and JAK3 for proliferation and survival. The critical nature of the gamma cytokine, JAK1/JAK3 pathway for ATL was supported by our observation that the ex vivo 6-day culture of PBMCs from patients with smoldering and chronic ATL could be inhibited by the administration of antibodies to the IL-2 receptor, as well as by the pan-JAK inhibitor, tofacitinib and the JAK1/2 inhibitor, ruxolitinib. To translate these observations, the Waldmann and Conlon Group has initiated a phase II clinical trial involving the JAK1/2 inhibitor, ruxolitinib in patients with ATL. To extend these studies with Craig Thomas we searched for novel multicomponent (combination) drug therapies for ATL by applying high-throughput matrix screening for cellular signaling on ATL cell lines to define combination therapies that identify agents with synergy. Optimal synergy was demonstrated between the JAK1/2 inhibitor, ruxolitinib added in association with the Bcl-xL inhibitor navitoclax. In molecular analyses our laboratory with Masao Nakagawa, a postdoctoral fellow, using RNA-seq identified nonsense mutations of CCR4 in 26% of the malignant cells of patients with ATL leukemic cells. In translation CCR4 is the target of a collaborative clinical trial involving patients with ATL using the anti-CCR4 monoclonal antibody, mogamulizumab. Furthermore, Dr. Liyanage Perera in the Waldmann Laboratory has generated an anti-CCR4 CAR for use in clinical trials of patients with ATL to take advantage of the over 90% CCR4 expression on ATL leukemic cells. In summary, the Waldmann Laboratory has made major contributions concerning the translation of molecular insights concerning ATL into new novel therapeutic strategies for this malignancy and a greater understanding of retroviruses mechanisms of action.

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Waldmann, Thomas A (2017) JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics. Mol Cell Endocrinol 451:66-70
Sharma, Kamal; Janik, John E; O'Mahony, Deirdre et al. (2017) Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1-Associated Adult T-cell Leukemia/lymphoma. Clin Cancer Res 23:35-42
Waldmann, Thomas A; Chen, Jing (2017) Disorders of the JAK/STAT Pathway in T Cell Lymphoma Pathogenesis: Implications for Immunotherapy. Annu Rev Immunol 35:533-550
Perera, Liyanage P; Zhang, Meili; Nakagawa, Masao et al. (2017) Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies. Am J Hematol 92:892-901
Mocsár, Gábor; Volkó, Julianna; Rönnlund, Daniel et al. (2016) MHC I Expression Regulates Co-clustering and Mobility of Interleukin-2 and -15 Receptors in T Cells. Biophys J 111:100-12
Yeh, Chien-Hung; Bai, Xue Tao; Moles, Ramona et al. (2016) Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia. Mol Cancer 15:15
Ju, Wei; Zhang, Meili; Wilson, Kelli M et al. (2016) Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or Navitoclax in a murine model of human Hodgkin's lymphoma. Proc Natl Acad Sci U S A 113:1624-9
Yeh, Chien-Hung; Bai, Xue Tao; Moles, Ramona et al. (2016) Erratum to: 'Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia'. Mol Cancer 15:20
Yokoyama, Seiji; Perera, Pin-Yu; Terawaki, Seigo et al. (2015) Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy in a Mouse Model of Autoimmune Lymphoproliferative Syndrome (ALPS). J Clin Immunol 35:661-7
Zhang, Meili; Mathews Griner, Lesley A; Ju, Wei et al. (2015) Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2-dependent adult T-cell leukemia. Proc Natl Acad Sci U S A 112:12480-5

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