Genetic or Pharmacological Reductions in DNA Methylation Selectively Inhibit Peripheral T-Cell Lymphomagenesis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2760-2760
Author(s):  
Jennifer J. Trowbridge ◽  
Mingjie Li ◽  
Charles W.M. Roberts ◽  
Stuart H. Orkin
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Cell Lymphoma ◽  
Dna Demethylation ◽  
T Cell Lymphoma ◽  
Demethylating Agents ◽  
Dna Methylation Inhibitors

Abstract Abstract 2760 The significance of mutations in components of the DNA methylation machinery in blood cancer has become a topic of intense investigation. Unlike genetic modifications, the reversible nature of DNA methylation and other epigenetic changes makes them attractive therapeutic targets. Very recently, mutations in the DNA methyltransferase DNMT3A and the DNA demethylase TET2 were identified in human peripheral T cell lymphoma (PTCL) [1]. These findings provided a novel link between the development and progression of PTCL with deregulation of DNA methylation processes. Importantly, this finding also extended the few known mutations associated with both T-cell lymphoma and myeloid leukemia. Our previous work identified acute sensitivity of MLL-AF9–induced myeloid leukemia (AML) to DNA demethylation through loss or haploinsufficiency of the DNA methyltransferase Dnmt1 [2]. Here, we investigated the sensitivity of PTCL to DNA demethylation. Lymphoma was induced in mice by inactivation of Snf5, a core subunit of the SWI/SNF chromatin remodeling complex, driven by CD4Cre (CD4Cre-Snf52lox). Inactivation of Snf5 leads to rapid onset of mature CD8+ PTCL with a median survival of 10 weeks of age. Strikingly, loss of Dnmt1 in this model (CD4Cre-Snf52lox-Dnmt12lox) completely abrogated development of lymphoma. Furthermore, haploinsufficiency of Dnmt1 was sufficient to increase event-free survival to 13 weeks of age (p=0.0008). Loss or haploinsufficiency of Dnmt1 did not impact normal T cell development in the thymus with the exception of a modest reduction in CD8+ CD44hi memory T cells. Based on the selective response of PTCL to reduced levels of Dnmt1 and DNA methylation, we screened a panel of pharmacological DNA demethylating agents for efficacy in PTCL. We found three putative DNA methylation inhibitors; the nucleoside inhibitor zebularine and non-nucleoside inhibitors RG108 and procainamide, which inhibited proliferation of primary murine PTCL in vitro. These inhibitors were effective at doses that did not restrict the proliferation of normal CD8+ T cells. When these inhibitors were evaluated for efficacy in vivo, both zebularine and procainamide were found to inhibit growth of primary murine PTCL. Together, these results suggest that therapy of PTCL with DNA methylation inhibitors or other DNA demethylating agents may achieve a favorable therapeutic index. Further, these results support the concept of a shared competitive advantage of myeloid leukemia and T-cell lymphoma in carrying mutations in the DNA methylation machinery. [1] Couronne L et al., NEJM, 2012, 366:95-6; [2] Trowbridge et al., Genes Dev, 2012, 26:344-9. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3062-3071 ◽  
Author(s):  
Qian Zhang ◽  
HongYi Wang ◽  
Kanchan Kantekure ◽  
Jennifer C. Paterson ◽  
Xiaobin Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cell ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Transcriptional Activity ◽  
Cell Lymphoma ◽  
Cpg Island ◽  
Methylation Status ◽  
T Cell Lymphoma ◽  
Growth Promoting

Abstract Here we report that T-cell lymphoma cells carrying the NPM-ALK fusion protein (ALK+ TCL) frequently express the cell-stimulatory receptor ICOS. ICOS expression in ALK+ TCL is moderate and strictly dependent on the expression and enzymatic activity of NPM-ALK. NPM-ALK induces ICOS expression via STAT3, which triggers the transcriptional activity of the ICOS gene promoter. In addition, STAT3 suppresses the expression of miR-219 that, in turn, selectively inhibits ICOS expression. ALK+ TCL cell lines display extensive DNA methylation of the CpG island located within intron 1, the putative enhancer region, of the ICOS gene, whereas cutaneous T-cell lymphoma cell lines, which strongly express ICOS, show no methylation of the island. Treatment of the ALK+ TCL cell lines with DNA methyltransferase inhibitor reversed the CpG island methylation and augmented the expression of ICOS mRNA and protein. Stimulation of the ICOS receptor with anti-ICOS antibody or ICOS ligand-expressing B cells markedly enhanced proliferation of the ALK+ TCL cells. These results demonstrate that NPM-ALK, acting through STAT3 as the gene transcriptional activator, induces the expression of ICOS, a cell growth promoting receptor. These data also show that the DNA methylation status of the intronic CpG island affects transcriptional activity of the ICOS gene and, consequently, modulates the concentration of the expressed ICOS protein.

Peripheral T-cell Lymphoma, NOS With Epstein-Barr Virus Positivity in an Elderly Patient With Myelodysplastic Syndrome: An Autopsy Case Report

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S81-S81
Author(s):  
J Lanceta ◽  
W Xue ◽  
M Hurford ◽  
H Wu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Barr Virus ◽  
Epstein Barr

Abstract Casestudy Epstein-Barr virus (EBV)-associated peripheral T-cell lymphomas are a group of aggressive neoplasms with a geographic predilection for South America and Asia, but are very rare in Western populations. Results We report a case of a 74-year-old Caucasian female who presented with pancytopenia and B symptoms with EBV-IgG detected on admission. Past medical history included: ITP, chronic urticaria, and recently diagnosed myelodysplastic syndrome (MDS) on bone marrow biopsy one month prior to admission. Excisional biopsies of an enlarged right neck lymph node (repeated within 6 months) and right axillary lymph node five years ago were negative for a lymphoproliferative disorder at the time. Repeated bone marrow biopsy, performed during the current admission, confirmed the diagnosis of MDS, with scattered T-cells without aberrant immunophenotype. Despite aggressive treatment from multiple specialties, the patient deteriorated and expired four weeks later from complications of MDS. At autopsy, there was diffuse lymphadenopathy involving the mediastinum, axilla, pelvis and peripancreatic fat. Lymph node sections demonstrated nodal architecture effacement by diffuse, vaguely nodular lymphoid infiltrates. Histologically, the infiltrates were composed of medium to large lymphocytes with round to slight irregular nuclei, rare Reed-Sternberg-like multinucleated cells, clumped chromatin, and indistinct nucleoli. Individual cell necrosis was abundant with mitotic figures readily identifiable. Immunohistochemistry revealed CD2+ CD3+ neoplastic T-cells that co-express MUM1 and a subset of CD30, while negative for CD4, CD5, CD8, CD56, ALK1, and TDT. EBV-encoded RNA in-situ hybridization was focally positive. The final postmortem diagnosis was peripheral T-cell lymphoma, not otherwise specified (NOS), with focal EBV positivity. Conclusion Co-existence of a de-novo MDS and non-Hodgkin lymphoma without any prior chemotherapeutic exposure is a highly unusual finding, although MDS-like presentations can occur with EBV-associated lymphomas. Peripheral T-cell lymphoma, NOS is an aggressive lymphoma and EBV positivity has been found correlated with a poor prognosis. This case demonstrates how postmortem examination remains an important tool in clinical- pathological correlation and highlights the potential pathogenetic role EBV plays in MDS and T-cell lymphoma.

scholarly journals Genome-Wide microRNA Expression Profiling in Molecular Subgroups of Peripheral T-Cell Lymphoma Identified Role of Mir-126 in T-Cell Lymphomagenesis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2767-2767
Author(s):  
Waseem Lone ◽  
Alyssa Bouska ◽  
Tyler Herek ◽  
Catalina Amador ◽  
Mallick Saumyaranajn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Ectopic Expression ◽  
T Cell Lymphoma ◽  
Molecular Subgroups ◽  
Peripheral T Cell Lymphoma ◽  
Tfh Cells

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas and approximately 30% of PTCLs are designated as not-otherwise specified (PTCL-NOS). Gene expression profiling (GEP) identified molecular classifiers for PTCL entities and identified 2 novel biological subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21), associated with T-cell differentiation subsets. To further investigate molecular oncogenesis, we performed microRNA expression profiling (miR-EP) in several molecular subtypes of PTCL including angioimmunoblastic T-cell lymphoma (AITL), PTCL-GATA3 and PTCL-TBX21 using formalin fixed paraffin embedded tissues. We also performed miR-EP of normal T-cell subsets polarized to represent different differentiation stages (TFH, TH1 and TH2). We performed miR-EP on 102 PTCL cases using either quantitative real time PCR (ABI, Biosystem) or ultra-sensitive direct miRNA counting (nCounter, NanoString). Corresponding GEP (mRNA) were available for 67 PTCL cases. Normal T-cells were polarized in-vitro with different cytokine milieu and examined by flow cytometry. We observed distinct miRNA profiles, with miRNA being uniquely expressed in TFH polarized cells (miR-26a-5p, miR-17-5p, miR-30d-5p, miR-22-3p, miR-222-3p, miR-142-3p, let-7i-5p and miR-29b-3p). In contrast, the TH1 lineage was enriched for expression of miR-155-5p, miR-146a-5p, miR-1246, miR-93-5p, miR-16-5p, miR-21-5p, miR-363-3p, miR-1260a, miR-186-5p, miR-148a-3p and miR-579-3p, whereas TH2 polarized cells expressed miR-181a-5p, let-7a-5p, miR-191-5p, miR-15b-5p, let-7d-5p, let-7b-5p, miR-140-5p, miR-98-5p, miR-423-5p and miR-630. Several of these miRNA expressed in the T-cells subsets showed corresponding expression in their respective PTCL entity such as miR-142-3p, let7i-5p, miR-21-5p and miR-29b-3p with AITL, miR-146-5p, miR-155-5p and miR-16-5p in PTCL-TBX21 and miR-181a-5p, miR-630 and let7a-5p in PTCL-GATA3. We also performed the MiRNA Enrichment Analysis and Annotation (miEAA) for miRNA signatures and observed an enrichment of miRNA regulating epigenetic modifications in TFH cells (p=0.028), whereas TH1 showed an enrichment of miRNA regulating IFN-g signaling (p=0.0024), and miRNA signatures in TH2 showed negative regulation of TGF-b signaling (p=0.023). Supervised analysis (p=0.05) of the miRNA profiles identified significant association of miR-126, miR-145, and let-7c-5p with AITL, when compared to other PTCLs. Similarly, miR-92a, miR-25, miR-636, miR-210, miR-222 and miR-491-5p significantly associated with PTCL-GATA3 and miRNA 126-3p, 145-5p, miR-26a-5p and miR-34a-5p associated with PTCL-TBX21. The miEAA for tumor miRNA signatures revealed enrichment of miRNAs regulating histone methylation (h3 k4 methylation) and chemokine receptor signaling in AITL, whereas miRNA regulating T-cell receptor were enriched in PTCL-TBX21 and TP53 signaling pathway in PTCL-GATA3. We validated the expression of miR-126 in AITL by qRT-PCR and also observed its increased expression in IL21 stimulated CD4+ T-cells. Ectopic expression of miR-126 resulted in a ~3 fold increased expression in T-cell lines and led to reduced proliferation and increased apoptosis with expression of T-cell exhaustion makers PD1 and TIM3. Computational algorithmic programs identified relevant biological targets of miR-126, including p85/PIK3R2, S1PR2 and DNMT3A that were further validated in-vitro. We observed an inverse correlation of miR-126 expression with S1PR2 expression (r=-0.64). S1PR2 is a crucial G protein-coupled receptor regulating B and T-cell migration in the germinal center (GC) reaction. Migration assays demonstrated significant decreases in T to B-cell migration, when B-cells (Raji) were co-cultured with Jurkat cells with ectopic expression of miR-126. With the GC reaction holding an important role in AITL, we investigated the biological significance of miRNA-126 in the context of the AITL microenvironment. High expression of miRNA-126 significantly associated with inferior survival in AITL (p=0.008) and significant differences in tumor microenvironment signatures. We identified distinct miRNA signatures for AITL and molecular subgroups of PTCL-NOS. Furthermore, elevated expression of miR-126 may contribute to the dysregulation and the homing of TFH cells in GC reaction through S1PR2 and warrants further mechanistic investigation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ectopic expression of a novel CD22 splice-variant regulates survival and proliferation in malignant T cells from cutaneous T cell lymphoma (CTCL) patients

Oncotarget ◽  
2015 ◽  
Vol 6 (16) ◽  
pp. 14374-14384 ◽  
Author(s):  
Ieva Bagdonaite ◽  
Hans H. Wandall ◽  
Ivan V. Litvinov ◽  
Claudia Nastasi ◽  
Jürgen C. Becker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Splice Variant ◽  
Cell Lymphoma ◽  
Ectopic Expression ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Malignant T Cells

scholarly journals Phase 1 Study of Subcutaneous Recombinant Human (rh) Interleukin-15 and Intravenous Alemtuzumab in Patients with Rrelapsed/Refractory T-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Milos D. Miljkovic ◽  
Kevin C Conlon ◽  
Jennifer Albert ◽  
Deborah Allen ◽  
Thomas A. Waldmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Interleukin 15 ◽  
Grade 3 ◽  
Dose Levels

BACKGROUND: Interleukin-15 (IL-15) is a member of the 4-α helix bundle family of cytokines. Administration of single-agent IL-15 to patients with cancer produced substantial increases and activation of natural killer (NK) cells and CD8+ T cells, but no clinical responses. Subsequent studies showed that IL-15 enhances the efficacy of anti-tumor monoclonal antibodies that work through antibody-dependent cell cytotoxicity, a process mediated by NK cells. In the MET-1 xenograft mouse model, the combination of IL-15 and the anti-CD52 antibody alemtuzumab led to significantly more durable responses than each agent by itself. Here we report the final results of the phase I trial of IL-15 and alemtuzumab in patients with relapsed and refractory T-cell lymphoma (NCT02689453). METHODS: In this phase I single-center trial IL-15 was given subcutaneously 5 days per week for 2 weeks in a standard 3+3 dose escalation scheme (DL1: 0.5μg/kg, DL2: 1μg/kg, DL3: 2μg/kg), followed by alemtuzumab 30mg intravenously three times weekly for 4 weeks. Primary endpoints were type and frequency of adverse events and the maximum tolerated dose of IL-15. RESULTS: A total of eleven patients (pts) were treated at DL1 (3), DL2 (4) and DL3 (4). Seven pts had acute adult T-cell leukemia (ATL), two had chronic ATL, and two had peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). There were no dose-limiting toxicities through the maximum planned dose of 2μg/kg/day. Two pts both with acute subtype ATL were unable to complete treatment due to rapidly progressive disease early in their treatment course, but there was no evidence tumor simulation or expansion of circulating ATL cell numbers during the period of IL-15 administration Hematologic AEs included lymphopenia (all 11 pts, 7 with grade 3/4), neutropenia (8 pts, 2 with grade 3), anemia (10 pts, 1 with grade 3), and thrombocytopenia (4 pts, 1 with grade 3). The most common non-hematologic AEs were infusion-related reactions experienced by 10 of the 11 pts during alemtuzumab infusion, and urticaria (4, pts, 2 with grade 3, both of whom at MTD). Two pts had incidental findings of a catheter-associated thrombus and pulmonary emboli, necessitating institution of prophylactic anticoagulation for subsequent pts after which no additional thromboembolic events were seen. Infectious adverse events included one case each of CMV reactivation without end-org involvement, HSV reactivation, Zoster, bacterial sinusitis, and cellulitis (in a patient with ATL and skin involvement), all grade 2. There was no evidence of graft versus host disease in two pts with previous allogeneic stem cell transplantation, and there were no serious adverse events attributable to IL-15. Administration of IL-15 resulted in a median 2.1-fold increase (range 1.2-3.4) in absolute lymphocyte count, 2.5-fold (1-5.9) increase in the number of circulating CD8+ T cells, and 7.2-fold (1.1-17.1) increase in NK cells across all dose levels (Figure 1A). At the MTD, the median ALC, CD8+ T cell, and NK cell increases were 2, 2.1, and 15.3-fold respectively. The overall response rate was 45% with 2/11 complete responses (CR) and 3/11 partial responses (PR) (Figure 1B). Notably, all pts with leukemic disease attained CR in the blood (Figure 1C), with varying response in other compartments. A patient with acute ATL had a CR at first restaging but developed central nervous system relapse after four weeks; this remained the only site of disease until the patient's death 8 months later. A patient with PTCL-NOS had a delayed response, with a PR at 3 and CR at 5 months which was ongoing at 12-month follow-up. Two pts with chronic ATL had PRs which lasted 10 and 4 months, and a patient with acute ATL had a PR at first restaging which was ongoing at the end of treatment. In all pts, response was correlated with normalization of serum LDH and soluble CD25. Analysis of peripheral blood mononuclear cells from responders and non-responders using single-cell RNA-seq is under way and will be presented. CONCLUSION: Combination of IL-15 and alemtuzumab was safe at all dose levels administered with no evidence of treatment related disease stimulation. The contribution of IL-15 to the known clinical efficacy of alemtuzumab in relapsed/refractory T-cell malignancies needs to be assessed in a randomized trial. Further evaluation of IL-15 in the post-allogeneic transplant setting, particularly prior to donor lymphocyte infusion, is also planned. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: alemtuzumab for T-cell lymphoma

scholarly journals Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma

2020 ◽  
Author(s):  
Darci Phillips ◽  
Magdalena Matusiak ◽  
Belén Rivero Gutierrez ◽  
Salil S. Bhate ◽  
Graham L. Barlow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Tumor Cells ◽  
Spatial Organization ◽  
Cell Lymphoma ◽  
Post Treatment ◽  
T Cell Lymphoma ◽  
T Cell Subsets ◽  
Cutaneous T Cell Lymphoma

Anti-PD-1 immunotherapies have transformed cancer treatment, yet the determinants of clinical response are largely unknown. We performed CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced cutaneous T cell lymphoma (CTCL) patients enrolled in a clinical trial of pembrolizumab therapy. Clinical response was not associated with the frequency of tumor-infiltrating T cell subsets, but rather with striking differences in the spatial organization and functional immune state of the tumor microenvironment (TME). After treatment, pembrolizumab responders had a localized enrichment of tumor and CD4+ T cells, which coincided with immune activation and cytotoxic PD-1+ CD4+ T cells. In contrast, non-responders had a localized enrichment of Tregs pre- and post-treatment, consistent with a persistently immunosuppressed TME and exhausted PD-1+ CD4+ T cells. Integrating these findings by computing the physical distances between PD-1+ CD4+ T cells, tumor cells, and Tregs revealed a spatial biomarker predictive of pembrolizumab response. Finally, the chemokine CXCL13 was upregulated in tumor cells in responders post-treatment, suggesting that chemoattraction of PD-1+ CD4+ T cells towards tumor cells facilitates a positive outcome. Together, these data show that T cell topography reflects the balance of effector and suppressive activity within the TME and predicts clinical response to PD-1 blockade in CTCL.

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