Adult T cell leukemia/lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). RNAi screening of ATLL lines revealed that their proliferation depends on BATF3 and IRF4, which cooperatively drive ATLL-specific gene expression. HBZ, the only HTLV-I encoded transcription factor that is expressed in all ATLL cases, binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including MYC. Inhibitors of bromodomain-and-extra-terminal-domain (BET) chromatin proteins collapsed the transcriptional network directed by HBZ and BATF3, and were consequently toxic for ATLL cell lines, patient samples, and xenografts. Our study demonstrates that the HTLV-I oncogenic retrovirus exploits a regulatory module that can be attacked therapeutically with BET inhibitors.
The leukocyte integrin gene, CD11c, is transcriptionally regulated and is expressed predominately on differentiated cells of the myelomonocytic lineage. In this study we have demonstrated that the regions ؊72 to ؊63 and ؊132 to ؊104 of the CD11c promoter contain elements responsible for phorbol ester-induced differentiation of the myeloid cell line HL60. DNase I footprinting analysis revealed that these regions can bind purified Sp1, and supershift analysis with Sp1 antibody confirmed that Sp1 in HL60 nuclear extracts could bind these regions. Transfection analysis of CD11c promoter-chloramphenicol acetyltransferase constructs containing deletions of these Sp1-binding sites revealed that these sites are essential for expression of the CD11c gene in HL60 cells but not in the T-cell line Molt4 or the cervical carcinoma cell line HeLa. Moreover, cotransfection of pP ac Sp1 along with these CD11c promoter-chloramphenicol acetyltransferase constructs into Sp1-deficient Drosophila Schneider 2 cells verified that these sites are essential for Sp1-dependent expression of the CD11c promoter. In vivo genomic footprinting revealed that Sp1 contacts the CD11c promoter within the regions ؊69 to ؊63 and ؊116 to ؊105 in phorbol 12-myristate 13-acetate-differentiated HL60 cells but not in undifferentiated HL60 cells or in Molt4 or HeLa cells. Cotransfection assays in HL60 cells revealed that Sp1 acts synergistically with AP1 to activate CD11c. Further, both Sp1 sites are capable of cooperating with AP1. In vitro DNase I footprinting analysis with purified Sp1 and c-jun proteins showed that Sp1 binding could facilitate binding of c-jun. We propose that myeloid-specific expression of the CD11c gene is, in part, a result of myeloid-restricted binding of Sp1 to the CD11c promoter and is facilitated by cooperative interaction between the Sp1-and AP1-binding sites.Myeloid cells (monocytes and granulocytes) participate in a variety of leukocyte-dependent functions within the immune system (2, 4, 15, 38). The action taken by myeloid cells following an immune response is mediated, in part, through genes that become activated during differentiation of pluripotent stem cells to myeloid cells. Activation of myeloid-specific genes is likely mediated, in part, by lineage-restricted transcription factors such as PU.1 (42, 52), Spi-B (43), MZF-1 (18), and NF-M (16).Among the myeloid-specific genes are those for the leukocyte integrins (26,29), specifically the CD11b (48) and CD11c (49) genes. These genes encode the alpha subunits of the dimeric receptors Mac-1 and p150,95, respectively. Differentiation of the myeloid cell lines HL60 and U937 with phorbol esters results in increased transcription of both genes (36, 39, 46). The transcription factor PU.1 was shown to be a major determinant for the expression of CD11b in myeloid cells (40), and recent results have revealed that Ap1 and Ets factors regulate CD11c (37). Particularly interesting was the observation that, in vivo, the ubiquitous transcription factor Sp1 was bound to the CD11b promote...
Purpose: The first-in-human clinical trial with human bolus i.v. infusion IL-15 (rhIL-15) was limited by treatment-associated toxicity. Here, we report toxicity, immunomodulation, and clinical activity of rhIL-15 administered as a 10-day continuous intravenous infusion (CIV) to patients with cancers in a phase I trial. Patients and Methods: Patients received treatment for 10 days with CIV rhIL-15 in doses of 0.125, 0.25, 0.5, 1, 2, or 4 mcg/kg/day. Correlative laboratory tests included IL-15 pharmacokinetic (PK) analyses, and assessment of changes in lymphocyte subset numbers. Results: Twenty-seven patients were treated with rhIL-15; 2 mcg/kg/day was identified as the maximum tolerated dose (MTD). There were 8 serious adverse events including 2 bleeding events, papilledema, uveitis, pneumonitis, duodenal erosions and 2 deaths (one due to likely drug-related gastrointestinal ischemia). Evidence of antitumor effects were observed in several patients, but stable disease was the best response noted. Patients in 2 mcg/kg/day group had a 5.8-fold increase in number of circulating CD8+ T cells, 38-fold increase in total NK cells, and 358-fold increase in CD56bright NK cells. Serum IL-15 concentrations were markedly lower during the last 3 days of infusion. Conclusion: This phase I trial identified the MTD for CIV rhIL-15 and defined a treatment regimen that produced significant expansions of CD8+ T and NK effector cells in circulation and tumor deposits. This regimen has identified several biological features, including dramatic increases in numbers of NK cells, supporting trials of IL-15 with anticancer monoclonal antibodies to increase antibody-dependent cell-mediated cytotoxicity (ADCC) and anticancer efficacy.
Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokinedependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.adult T-cell leukemia | Janus kinase | ruxolitinib | navitoclax T -cell leukemia/lymphoma represents ∼10% of lymphoid malignancies. Genetic alterations affecting members of the Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) were discovered in a variety of T-cell malignancies (1, 2). Furthermore, increases in the common γc cytokine concentrations that signal through the JAK1/3, STAT3/5 pathway have been demonstrated in angioimmunoblastic T-cell lymphoma, gamma delta T-cell lymphoma, and adult T-cell leukemia (ATL), thereby identifying effective therapeutic targets.ATL is an aggressive T-cell malignancy characterized by the clonal expansion of CD4 + CD25 + T lymphocytes that develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1 (HTLV-1) (3-5). Clinically, ATL is subclassified into four subtypes: smoldering, chronic, lymphomatous, and acute (4, 5). Presently, there is no curative therapy for ATL (4, 5). In search of effective therapies, we examined key signaling pathways that confer a proliferation and viability advantage to ATL cells. It was noted that the HTLV-1-encoded Tax (transactivator from the X-gene region) is associated with increased Bcl-xL (B-cell lymphoma-extra large) expression in ATL cells (6). Furthermore, we reported two autocrine loops (IL-2/IL-2Rα, IL-15/IL-15Rα) and one paracrine loop that in...
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