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

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.

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DNMT3A Mutations Identify a Prognostic Subgroup in Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood-2020-143335 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 38-39

Author(s):

Tyler A. Herek ◽

Alyssa Bouska ◽

Waseem G. Lone ◽

Tayla B. Heavican ◽

Catalina Amador ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Cell Lymphoma ◽

Ectopic Expression ◽

T Cell Lymphoma ◽

Cytotoxic T Cell ◽

Wild Type ◽

Tcr Signaling ◽

Peripheral T Cell Lymphoma

Background Mutational profiling of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) has revealed recurrent mutations in DNMT3A, a de novo methyltransferase. DNMT3A catalyzes the conversion of cytosine to 5-methylcytosine (5-mC) while interacting with histones and transcription factors to influence gene expression. While the DNMT3A mutational profile in PTCL entities indicates loss-of-function, hotspot change-of-function mutations (e.g., DNMT3AR882H/C) have been observed with their frequency differing between PTCL entities. Despite the high occurrence of DNMT3A mutations in PTCLs (~30% of cases), their functional consequences have not been extensively studied. Herein, we examined DNMT3A mutations in AITL and the novel molecular subgroups of PTCL-NOS (i.e., PTCL-TBX21 and PTCL-GATA3) and observed distinct biological and prognostic significance associated with DNMT3A mutations in the PTCL-TBX21 subgroup. Methods PTCL-NOS cases (n = 141) were utilized following PTCL-TFH exclusion. Using previously described molecular classification methods, cases were classified as PTCL-TBX21 (n = 80) or PTCL-GATA3 (n = 61). A separate cohort of AITL cases (n = 176) were included for comparative purposes. Clinical outcome data were assessed with the Kaplan-Meier method. Mutation data were generated from DNA-sequencing (n = 224) or RNA-sequencing methods (n = 46). Gene expression comparisons were conducted using BRB-ArrayTools. Immune-cell signatures were generated from the CIBERSORT and/or xCell computational tools. 5-mC DNA immunoprecipitation sequencing (MeDIP-Seq) was performed on available PTCL-TBX21 cases (n = 7) or healthy tonsil controls (n = 2). Four of these cases carried DNMT3A mutations (n = 3 DNMT3AR882, n = 1 DNMT3AQ886) while the remaining cases (n = 3) were wild type for DNMT3A. In vitro analyses of ectopic expression of the DNMT3AR882H mutant or DNMT3A knockdown were conducted using healthy-donor CD3+ T-cells or the CD8+ T8ML1 PTCL cell line. Following corrections for false discoveries, p-values < 0.05 were considered significant. Results DNMT3A-mutated PTCL-TBX21 cases had an inferior overall survival, with DNMT3A mutated residues skewed toward the methyltransferase domain. In contrast to the DNMT3A mutation profile seen in AITL, PTCL-TBX21 featured DNMT3AR882H/C mutations at a frequency (30%) similar to other hematological malignancies. Gene expression profiling revealed that DNMT3A-mutant PTCL-TBX21 cases were enriched for activated CD8+ T-cell gene signatures and showed association with the previously described TH1/αβ cytotoxic T-cell lymphoma subgroup. Following MeDIP-Seq, assessment of differentially methylated regions comparing DNMT3AR882/Q886 PTCL-TBX21 cases to wild type found hypomethylation in pathways associated with T-cell activation, TCR signaling, and TH1 responses. In vitro analyses demonstrated that ectopic expression of the DNMT3AR882H mutant or DNMT3A knockdown lead to enhanced proliferation and NF-κB signaling in T8ML1 cells in comparison to control vectors. In primary CD3+ T-cell cultures, ectopic expression of the DNMT3AR882H mutant protein resulted in the preferential outgrowth of CD8+ T-cells. Conclusions Taken together, our findings establish mutations in DNMT3A as a novel prognostic marker in PTCL-TBX21. The integrated expression, methylation, and in vitro findings suggest that disruption of DNMT3A leads toward an activated and cytotoxic phenotype and could potentially drive oncogenic TCR signaling. Clinically, as these cases were associated with the TH1/αβ cytotoxic T-cell lymphoma subgrouping, these findings should be taken into consideration for future treatment strategies regarding PTCL-NOS patients as current standard-of-care treatments may be particularly inadequate in the treatment of PTCLs with cytotoxic phenotype. Disclosures No relevant conflicts of interest to declare.

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Genome-wide microRNA expression profiling of molecular subgroups of peripheral T-cell lymphoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-21-0573 ◽

2021 ◽

pp. clincanres.0573.2021

Author(s):

Waseem Lone ◽

Alyssa Bouska ◽

Sunandini Sharma ◽

Catalina Amador ◽

Mallick Saumyaranjan ◽

...

Keyword(s):

T Cell ◽

Expression Profiling ◽

Cell Lymphoma ◽

Microrna Expression ◽

T Cell Lymphoma ◽

Molecular Subgroups ◽

Peripheral T Cell Lymphoma ◽

Genome Wide

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

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.178 ◽

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.

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

Oncotarget ◽

10.18632/oncotarget.3720 ◽

2015 ◽

Vol 6 (16) ◽

pp. 14374-14384 ◽

Cited By ~ 2

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

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The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells

Blood ◽

10.1182/blood-2006-10-055145 ◽

2007 ◽

Vol 109 (11) ◽

pp. 4952-4963 ◽

Cited By ~ 375

Author(s):

Laurence de Leval ◽

David S. Rickman ◽

Caroline Thielen ◽

Aurélien de Reynies ◽

Yen-Lin Huang ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Gene Set Enrichment Analysis ◽

Molecular Profile ◽

Peripheral T Cell Lymphoma ◽

Angioimmunoblastic T Cell Lymphoma ◽

Tfh Cells ◽

Follicular Helper

Abstract The molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ontogeny and molecular differences between both entities, a series of AITLs (n = 18) and PTCLs-u (n = 16) was analyzed using gene expression profiling. Unsupervised clustering correlated with the pathological classification and with CD30 expression in PTCL-u. The molecular profile of AITLs was characterized by a strong microenvironment imprint (overexpression of B-cell– and follicular dendritic cell–related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T (TFH) cells (CXCL13, BCL6, PDCD1, CD40L, NFATC1). By gene set enrichment analysis, the AITL molecular signature was significantly enriched in published TFH-specific genes. The enrichment was higher for sorted AITL cells than for tissue samples. Overexpression of several TFH genes was validated by immunohistochemistry in AITLs. A few cases with molecular TFH-like features were identified among CD30− PTCLs-u. Our findings strongly support that TFH cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30− PTCLs-u may derive from or be related to AITL.

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CD4+/bcl-6+ Peripheral T-Cell Lymphoma with Follicular Involvement: A Distinct Type of Nodal Peripheral T-Cell Lymphoma with Multiple T-Cell Clones.

Blood ◽

10.1182/blood.v104.11.1374.1374 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1374-1374

Author(s):

Ida Munster-Ikonomou ◽

Anne Tierens ◽

Gunhild Troen ◽

Hege Aamodt ◽

Sverre Heim ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Lymphoma Cells ◽

Peripheral T Cell Lymphoma ◽

Lymphoid Follicles ◽

B Lymphoid ◽

Lymphoma Type

Abstract We studied six cases of a novel type of nodal peripheral T-cell lymphoma. Three cases with this disease were recently described by de Leval et al. (de Leval L, Savilo E, Longtine J, et al. Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype. Am J Surg Pathol2001;25:395–400). The entity was named peripheral T-cell lymphoma with follicular involvement because of its distinctive histological features. We report an additional six well-characterized cases and describe the molecular and cytogenetic findings. The neoplastic T-cells of this lymphoma type express CD4 and Bcl-6, and home to the B-lymphoid follicles. This suggests an origin of the lymphoma from an as yet poorly characterized subset of Bcl-6 expressing intra-follicular T-helper cells. Of interest, the cytogenetic data and/or the study of T-cell receptor gamma gene rearrangements revealed more than one clone in each case. Cytogenetics further revealed complex karyotypes without recurrent chromosomal aberrations. We also studied the presence of somatic mutations in the 5′ untranslated region of the BCL-6 gene in four of the cases but no somatic hypermutation was detected. Clinically, the cases presented with widespread lymph node involvement at diagnosis and multiple relapses occurred after treatment. All patients received a CHOP-based chemotherapy regimen, later followed by high dose chemotherapy with stem cell rescue in five patients. One patient died with lymphoma and hemophagocytic syndrome 24 months after diagnosis, one patient is alive with disease after 27 months from diagnosis, whereas the other four patients are in complete remission 12 to 124 months after diagnosis. In conclusion, we confirm that peripheral T-cell lymphoma with follicular involvement is a distinct lymphoma type and we show that the lymphoma is oligo-clonal. The clinical findings are those of an intermediately aggressive lymphoma type. Although minimal lymph node infiltration with lymphoma cells at diagnosis and oligo-clonality is also characteristic of angio-immunoblastic T-cell lymphoma, we believe that peripheral T-cell lymphoma with follicular involvement is a distinct T-cell lymphoma type. In contrast to angio-immunoblastic T-cell lymphoma it is characterized by the typical infiltration of lymphoma cells in B-lymphoid follicles, coagulation necrosis, the absence of proliferation of high endothelial venules and follicular dendritic cells in T-cell areas, as well as the absence of EBV infection. It is likely that T-cell lymphoma with follicular involvement arises from Bcl-6+ intra-follicular T-cells. No recurrent genetic defects have been identified but the oligo-clonal nature of the lymphoma is intriguing. The latter suggests that the triggering oncogenic factors are external, such as infection.

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Molecular Signatures to Improve Diagnosis, Prognostication and Identification of Oncogenic Pathways in Peripheral T and NK Cell Lymphoma.

Blood ◽

10.1182/blood.v112.11.3339.3339 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3339-3339

Author(s):

Javeed Iqbal ◽

Dennis Weisenburger ◽

Timothy C. Greiner ◽

Shigeo Nakamura ◽

Julie M. Vose ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Nk Cell ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Molecular Signatures ◽

Peripheral T Cell Lymphoma ◽

Host Interactions ◽

Oncogenic Pathways

Abstract Background: Peripheral T-cell lymphoma (PTCL) consists of an uncommon and heterogeneous group of lymphomas that are often challenging to diagnose and classify. Since most patients also have a poor survival with standard multiagent chemotherapy, more effective therapeutic approaches are needed to improve patient outcome. Table1: Pathological diagnosis Number of cases profiled AITL 36 ALK(+)ALCL 19 ALK (−)ALCL 08 ATLL 12 T/NK 14 PTCLU 44 Other rare entities 10 Methods: A mRNA profiling study using Affymetrix HGU133+2 arrays on 143 cases of PTCL and NK-cell lymphoma (NKCL) from the International Peripheral T-cell Lymphoma Project, was conducted on pre-treatment biopsies. These included the following pathologically classified cases (Table 1). In addition, we also profiled nine NK cell lines, seven T cell lines, normal resting and activated CD4+ and CD8+ T cells and resting and IL2- activated NK cells from healthy individuals. BRB-ArrayTools was used to develop gene classifiers for the major PTCL entities and survival predictors for AITL based on gene expression data. Results: We have identified key molecular signatures for PTCL and NKCL that have allowed us to construct a robust classifier for AITL (207 transcripts), ALK+ ALCL (94), ATLL (225) and NKCL (127). PTCL-U group may have 3 or 4 molecular subgroups and additional studies with more cases, are necessary to further define this group. Misclassified cases were identified and re-assigned to the molecularly defined entities, including re-assigning of 9/44 PTCL-U to AITL. We have confirmed the enriched expression of genes identified in follicular helper T-cells in AITL, suggesting that AITL is derived from this T-cell subset. A number of oncogenic pathways (e.g. NF-κB, HIF-a,VEGF, IL6) and tumor/host interactions that contributed to local tumor-induced immunosuppression (e.g. TGF-b), were identified in AITL. A molecular predictor of outcome was developed for AITL and validated by leave one-out-cross validation. Since PTCL is an uncommon disease, future studies will require the collaboration of multiple large clinical groups with tissue resources for both discovery and validation. Conclusion: This study has demonstrated that GEP will allow the construction of robust and biologically-meaningful classifiers for PTCL, and prognosticators can be derived for well-defined entities with a sufficient number of cases. GEP will also allow us to identify therapeutically-relevant oncogenic pathways and tumor/host interactions that may lead to improvement in the therapy and outcome of patients with PTCL and NKCL. (This study is a part of the International T-cell Lymphoma Project)

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Enforced Expression of Lin28b Drives Development of Peripheral T Cell Lymphoma In Vivo

Blood ◽

10.1182/blood.v118.21.1392.1392 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1392-1392 ◽

Cited By ~ 1

Author(s):

Sarah H Beachy ◽

Masahiro Onozawa ◽

Yang Jo Chung ◽

Christopher Slape ◽

Sven Bilke ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Cell Lymphoma ◽

Regulatory Elements ◽

T Cell Lymphoma ◽

Effector Memory ◽

Peripheral T Cell Lymphoma ◽

Chronic Inflammatory Condition

Abstract Abstract 1392 Lin-28 was first identified as a heterochronic gene in C. elegans and is expressed at high levels during early larval stages with dramatically decreased expression in subsequent developmental stages. Interestingly, recent work demonstrated that induced expression of LIN28 can reprogram human fibroblasts to acquire pluripotency (in combination with NANOG, OCT4 and SOX2), providing additional evidence for a positive correlation between LIN28 expression and maintenance of a more immature and stem cell-like developmental state. Lin28a and Lin28b, the mammalian homologues of lin-28, have been implicated in oncogenic transformation in a variety of tumor types, in part by their ability to promote the degradation of the let-7 family of microRNAs (miRs), which are known to target oncogenes such as Myc and Ras. We recently noted that Lin28b was markedly overexpressed in hematopoietic tissues of NUP98-HOXD13 (NHD13) transgenic mice that develop a myelodysplastic syndrome (MDS) that subsequently transforms to acute myeloid leukemia (AML) or pre-T lymphoblastic leukemia/lymphoma (pre-T LBL). In order to elucidate the contribution of Lin28b overexpression to the differentiation block and malignant phenotype observed in the NHD13 mice, we designed a Lin28b transgenic mouse by targeting the expression of the transgene to hematopoietic tissues with Vav regulatory elements. In this model, clinically healthy Lin28b mice exhibited aberrant thymic architecture and retention of thymocytes that was correlated with peripheral blood lymphopenia (a 2.6-fold decrease in circulating lymphocytes). The lymphopenia was principally due to decreased numbers of CD4+ and CD8+ cells, although there was a significant increase in the number of CD4 and CD8 effector memory T cells (CD44hiCD62Llo) compared with wild type mice. Additionally, deep sequencing of thymic miRs from clinically healthy transgenic mice revealed a 2–5-fold downregulation of let-7 family members, including let-7d, g, f, i and miR-98. Importantly, with age, the Lin28b mice developed an aggressive, lethal, peripheral T cell lymphoma (PTCL), characterized by widespread infiltration of parenchymal organs with a mixed infiltrate of inflammatory cells and malignant CD4+ T cells. Clonal Tcrb gene rearrangements were observed in the lymphomas and the malignant cells engrafted and formed tumors in immunodeficient Scid mice. The Lin28b transgenic mice also had clinical signs consistent with a chronic inflammatory condition, such as eosinophilia, anemia, pleural effusions and ascites. The lymphomas overexpressed Il6 and Myc, and activated Nfκb, demonstrating in vivo involvement of a previously reported pathway that links Lin28b expression with inflammation and malignant transformation. Analysis of a publically available dataset indicated that Lin28b was overexpressed by 8-fold in a set of PTCL patient samples compared with activated CD4+ cells. Taken together, these findings demonstrate in vivo evidence for an oncogenic function of Lin28b and provide a model for further study of both the biology and identification of new therapeutic targets for PTCL, a heterogenous disease with poor prognosis. Disclosures: No relevant conflicts of interest to declare.

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PLZF Staining Identifies Peripheral T-Cell Lymphomas Derived From Non-Conventional T-Cells With Limited α-Chain Diversity

Blood ◽

10.1182/blood.v122.21.4300.4300 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4300-4300

Author(s):

Stephanie McGregor ◽

Anant Shah ◽

Gordana Raca ◽

Kamran Mirza ◽

John Anastasi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Innate T Cells ◽

T Cell Lymphomas ◽

Α Chain ◽

Peripheral T Cell Lymphomas

Abstract Peripheral T-cell lymphomas are uncommon and account for 10-15% of all non-Hodgkin lymphomas (NHL). The current classification and treatment strategy of peripheral T-cell lymphomas relies on integrating morphology with immunophenotype, genetics and clinical presentation. However, the most common category of peripheral T-cell lymphomas remains peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) reflecting the lack of specific parameters to better define these lymphomas in a biologically relevant way. As our understanding of the biology of peripheral T-cell development continues to improve, several immunophenotypic markers have become available that can delineate peripheral T-cells into functional subsets. It is now recognized that peripheral T-cell lymphomas can arise from both conventional and innate-like T-cells. Classically, peripheral lymphomas with the γδ T-cell receptor (TCR) as well as lymphomas derived from true natural killer (NK) cells are considered to be arising from the innate T-cells whereas T-cell lymphomas with an αβ TCR are assumed to be derived from the adaptive, conventional T-cells. However, several recent studies have identified relatively rare populations of αβ T cells with extremely limited α chain diversity. These T-cells are characterized by the ability to mount immune responses by interacting with non-classical MHC class I antigen presenting molecules even in the absence of intentional priming. The cells within these populations express markers characteristic of NK cells and/or memory T-cells and include cells frequently labeled as “NKT” cells and mucosal-associated invariant T-cells (MAIT). Whether these cells contribute to peripheral T-cell lymphomas is not known. The transcription factor promyelocytic leukemia zinc finger (PLZF) is indispensable for development and maturation of these T-cells. We therefore asked the question whether PLZF expression could be used to identify peripheral T-cell lymphomas derived from these innate like non-conventional T-cells. To answer this question, we generated a tissue microarray that included biopsies from 26 PTCL-NOS, 11 anaplastic large cell lymphomas (ALCL), ALK-, and 13 ALCL, ALK+. Histologically normal tonsil, lymph node, thymus and gastrointestinal biopsies were used as controls. Immunohistochemistry with the PLZF antibody was performed in the clinical immunohistochemistry laboratory. Only rare PLZF positive cells were observed in uninvolved tonsils, lymph nodes, and thymus. In contrast, the intestinal mucosa, which is normally enriched in PLZF positive innate type T-cells showed a relative abundance with expression observed in 8-10% lymphocytes. Lymphomas were scored as positive when 20% or more of tumor cells showed expression with nuclear localization. Within the lymphomas, PLZF expression was observed in 2/26 PTCL-NOS and 2/13 ALCL, ALK+. PLZF expression was not observed in any of the ALCL, ALK- lymphomas included in the current study. PCR amplification followed by sequencing identified the Vα7.2-Jα33 TCR rearrangement characteristic of the MAIT cells in the two PLZF positive PTCL-NOS lymphomas confirming the origin of these lymphomas from bona fide innate-like T-cells. Sequencing of the TCR in the remaining three PLZF positive lymphomas is currently in progress. Cytogenetic analysis was available in three of the 4 cases. While t(2;5) was the sole cytogenetic abnormality in one ALCL, ALK+ lymphoma, the remaining two cases, including one ALCL, ALK+ had a complex karyotype that included t(2;5). In view of the relatively small number of patients available for analysis and the heterogeneous therapy administered to patients included retrospectively in the study, an outcome analysis was not performed. In conclusion, we demonstrate that PLZF expression identifies lymphomas derived from non-conventional innate-like T-cells and likely represent a biologically unique group of peripheral T-cell lymphoma. It is well known that innate T-cells are highly resistant to xenobiotics due to high expression of the transporter ATP binding cassette B1 (MDR). Prospective evaluation for PLZF expression may therefore be useful in identifying patients who will benefit from therapy that specifically targets this pathway of drug resistance. Disclosures: No relevant conflicts of interest to declare.

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A novel lncRNA TCLlnc1 promotes peripheral T cell lymphoma progression through acting as a modular scaffold of HNRNPD and YBX1 complexes

Cell Death and Disease ◽

10.1038/s41419-021-03594-y ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Ping Zhao ◽

Meng-Meng Ji ◽

Ying Fang ◽

Xiao Li ◽

Hong-Mei Yi ◽

...

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

T Cell Lymphoma ◽

Small Interfering Rnas ◽

Transcription Activator ◽

Peripheral T Cell Lymphoma

AbstractLong noncoding RNAs (lncRNAs) play an essential role in tumor progression. Few researches focused on the clinical and biological relevance of lncRNAs in peripheral T cell lymphoma (PTCL). In this research, a novel lncRNA (ENST00000503502) was identified overexpressed in the main subtypes of PTCL, and designated as T cell lymphoma-associated lncRNA1 (TCLlnc1). Serum TCLlnc1 was associated with extranodal involvement, high-risk International Prognostic Index, and poor prognosis of the patients. Both in vitro and in vivo, overexpression of TCLlnc1 promoted T-lymphoma cell proliferation and migration, both of which were counteracted by the knockdown of TCLlnc1 using small interfering RNAs. As the mechanism of action, TCLlnc1 directly interacted with transcription activator heterogeneous nuclear ribonucleoprotein D (HNRNPD) and Y-box binding protein-1 (YBX1) by acting as a modular scaffold. TCLlnc1/HNRNPD/YBX1 complex upregulated transcription of TGFB2 and TGFBR1 genes, activated the tumor growth factor-β signaling pathway, resulting in lymphoma progression, and might be a potential target in PTCL.

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