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

Blood ◽  
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)

Gene Expression Profiling Reveals Activation of Multiple Oncogenic Pathways and Over-Expression of Survivin in the Pathogenesis of Extranodal Nasal-Type NK/T Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3931-3931
Author(s):  
Wee-Joo Chng ◽  
Viknesvaran Selvarajan ◽  
Gaofeng Huang ◽  
Jianbiao Zhou ◽  
Mark Law ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Cell Lines ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Nasal Type ◽  
Over Expression ◽  
Natural Killer T Cell ◽  
Oncogenic Pathways

Abstract Abstract 3931 Poster Board III-867 Extranodal nasal-type Natural Killer/T-cell lymphoma (NKTCL) is a distinct clinicopathologic entity most commonly affecting Asians and Central and South Americans, and characterized by a clonal proliferation of NK or T cells with a cytotoxic phenotype. There is a strong association with Epstein-Barr Virus. The tumor is aggressive with patient usually surviving short duration even with chemotherapy. We performed the first comprehensive genome-wide gene expression profiling (GEP) of extranodal nasal-type Natural Killer/T-cell lymphoma (NKTCL) using formalin-fixed paraffin embedded (FFPE) tissue (n=25) and NK cell lines (n=5) and compared the results to the GEP of normal NK cells using the Illumina DASL whole genome array, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTCL and to identify potential therapeutic targets. Quantitative-PCR validation of the GEP findings revealed over-expression of candidate genes BIRC5 (survivin), EZH2 and STMN1 in NK cell lines compared to normal NK cells, consistent with the GEP data. We then extracted a list of genes that are differentially expressed between NKTCL and normal NK cells and tissue controls. We than subjected this list of genes to pathway and network analysis using Metacore. This revealed a significant enrichment for cell cycle related genes and pathways. Furthermore, the network analysis results demonstrated a pro-proliferative and anti-apoptotic phenotype in NKTCL characterized by activation of Myc and nuclear factor kappa B (NF-KB), and deregulation of p53. This was further corroborated using immunohistochemistry on tissue microarray of NKTCL (n=33, including all cases with GEP performed). We observed a significant percentage of NKTCL showing overexpression for c-Myc (45.4%), p53 (87.9%) and NF-KB p50 (67.7%) on immunohistochemistry. Notably, overexpression of survivin was observed in 97% of the cases. Based on our findings, we propose a model of NKTCL pathogenesis where deregulation of p53 together with activation of MYC and NF-KB, possibly driven by EBV LMP-1, result in the cumulative upregulation of survivin. When KHYG and NKYS cell lines were treated with a compound IDR E804 which inhibited survivin, there is significant inhibition of cell growth as assess by MTS assay and induction of apoptosis as measured using Annexin V staining by flow cytometry. This suggests that compounds inhibiting survivin may be a potentially useful novel therapeutic approach in NKTCL. Disclosures: No relevant conflicts of interest to declare.

NK-Cell Lymphoma Shares Strikingly Similar Molecular Features with a Distinct Set of γδ T-Cell Lymphoma and Identification of Aurora Kinase A Inhibitor as a Novel Therapeutic Agent.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 313-313
Author(s):  
Javeed Iqbal ◽  
Dennis D. Weisenburger ◽  
Aparajita Chowdhury ◽  
Gopesh Srivastava ◽  
Timothy C. Greiner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Aurora Kinase ◽  
T Cell Lymphoma ◽  
Γδ T Cell ◽  
Aurora Kinase A ◽  
Kinase A

Abstract Abstract 313 Background: Natural Killer (NK) cell lymphomas (NKCL) are rare with aggressive clinical behavior. The majority of these cases belong to extra-nodal NK/T-cell lymphoma of nasal type (ENKTL) of the current World Health Organization (WHO) classification scheme. ENKTL also includes peripheral T-cell lymphomas (PTCL) that are similar in many respects to the NK cell counterpart. Due to rarity of the disease and difficulty in obtaining adequate biopsy specimens, the molecular mechanisms underlining ENKTL are largely unknown. We profiled a series of NK-cell lymphoma cases and many well- characterized cell lines of NK- and T-cell lineages to define molecular classifiers that can distinguish NKCL from PTCL, including lymphomas of cytotoxic T-cells. We also evaluated oncogenic pathways in these tumors and the therapeutic potential of a novel inhibitor of a cell cycle regulator (aurora kinase A). Patients and Methods: The gene expression profiling (GEP) of ENKTL (n=21) and PTCL-U (n=50) cases were performed using HG U133 plus 2 arrays (Affymetrix Inc, CA). GEP of other PTCL subtypes (n=90), normal NK and T cells (resting and activated), NK and T cell lines (n=14) and indolent NK- cell/large granular lymphocytic proliferation (NK-LGLP) (n=5) were used for comparative analysis. Immunohistochemistry (IHC) was used to validate the GEP findings. A novel aurora-kinase-A inhibitor (MK-8745) was obtained from Merck & Co (Merck & Co., Inc. NJ, USA) and incubated with the cell lines for 2 -24 hours at 0.1-1 μM concentrations. Results: The ENKTL showed a male predominance (2:1) with a median age of 55 years at diagnosis and aggressive clinical behavior [5-year OS (<10%)]. Unsupervised hierarchical clustering revealed that ENKTL cases formed a distinct cluster from PTCL entities, with a few PTCL-U cases interspersed in the cluster. The molecular classifier derived for NKCL was composed of 84 transcripts. The majority of the upregulated genes demonstrated the distinct phenotypic and functional characteristics associated with NK-cells, including expression of many cytotoxic molecules and NK cell associated chemokines. The down-regulated genes were largely associated with T-cell biology including T-cell activation and maturation. Most of the classifier genes were contributed by the neoplastic cells, not by stromal cells, as these genes showed similar pattern in normal NK cells and NK cell lines. Surprisingly, three γδ T-cell lines and five PTCL-U cases were re-classified as NKCL. The gene expression profile of these cases was very similar to NKCL but further analysis demonstrated that they expressed genes associated with TCR complex including TCR -γ,-δ, CD3 -γ and -δ mRNA, thus exhibiting γδ T-cell differentiation. Further pathological review indicated that all these tumors showed extranodal involvement and the expression of γδ TCR. These γδ PTCLs could be distinguished readily from a group of (αβ) cytotoxic PTCL and hepatosplenic T-cell lymphoma (HSTCL) by GEP and in the usage of the TCR V region. Pathway analysis revealed enrichment of gene signatures related to TGFβ and VEGF pathway and high proliferation in NKCL, when compared with IL-2 activated normal NK-cells or NK-LGLP. Due to high-proliferation associated with NKCL a mitotic inhibitor was tested. All NK-cell lines were highly sensitive to aurora kinase A inhibitor with a significant increase in apoptosis and cell cycle arrest at G2/M phase. There was concomitant decrease in phosphorylated aurora kinase-A and Survivin levels with induction of TP53. Conclusion: The NKCL molecular classifier identified lymphomas of NK-cell origin as well as a unique subset of γδ T cell lymphoma. These tumors are derived from cytotoxic cells of the innate immune system associated with epithelial surfaces. They have a different GEP from the T-cell lymphomas derived from αβ cytotoxic T-cell and even other γδ T cell lymphoma such as HSTCL which may be derived from an ontogenically and functionally distinct subset of γδ T cells. The role of enriched pathways in NKCL pathogenesis and biology requires further investigation. The effectiveness of the Aurora-kinase A inhibitor in inducing apoptosis of NK-cell lines suggests that it may be a candidate for use in clinical trials in NKCL. Disclosures: No relevant conflicts of interest to declare.

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.

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 ◽  
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.

The Role of Mir-150 as a Tumor Suppressor In Malignant Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 465-465
Author(s):  
Atsushi Watanabe, ◽  
Hiroyuki Tagawa ◽  
Kazuaki Teshima ◽  
Yoshihiro Kameoka ◽  
Naoto Takahashi ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Telomerase Activity ◽  
Akt Signaling ◽  
T Cell Lymphoma ◽  
Nk T Cell

Abstract Abstract 465 Disease specific genetic alteration or translocation have not been identified in NK/T cell lymphoma. We recently demonstrated that over expressions of miR-21 and/or miR-155 are frequently occurring in natural killer (NK) cell lymphoma/leukemia and deeply associated with their lymphomagenesis by deregulation of AKT signaling. In this study, we tried to identify tumor suppressor miRNA(s) in malignant lymphomas including B-cell, NK-cell and CD4+T-cell lymphoma, by using quantitative PCR and/or Northern blot analysis. We found that miR-150 in both cell lines and primary samples of NK and T-cell lymphoma showed significantly lower expression than those of normal natural killer cells and CD4+T cells. To examine the role for lymphomagenesis, we stably transduced miR-150 into lymphoma cell lines. Enforced expression of miR-150 in NK/T cell lymphoma cell lines showed increased levels of susceptibility of apoptosis, and showed senescence with reduced levels of telomerase activity and telomere DNA shortening. We further demonstrated that miR-150 directly down regulate AKT2, leading to reduced expression of phosphorylated AKTser473/474 with upregulation of tumor suppressors, Bim, p27 and p53. Since it has been proven that AKT kinase phosphorylate hTERT (human telomerase reverse transcript), downregulation of miR-150 in lymphomas lead to activate telomerase activity, resulting immortalization of the cancer cells. These results suggest that miR-150 play as a role of tumor suppressor in NK/T-cell lymphoma. Our recent and previous report demonstrate that downregulation of miR-150 and upregulation of miR-21/miR-155 collaborately contribute to NK/T-cell lymphomagenesis by deregulating AKT signaling. These findings will give a new insight into the pathogenesis of NK/T cell lymphoma and the miR-150 itself and/or AKT targeting therapy can be a useful against aggressive lymphoma. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1392-1392 ◽  
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.

Combined Effect of Mtor Inhibitors and FTI for the Growth Inhibition of T Cell Lymphoma - Involvement of Different Molecular Mechanisms According to the Lymphoma Subtype

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4870-4870
Author(s):  
Leonidas Zierock ◽  
Wolfgang Melchinger ◽  
Bettina Wehrle ◽  
Juergen Finke ◽  
Reinhard Marks
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Cd4 T Cells ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
Mtor Inhibitors ◽  
T Cell Lymphoma ◽  
Ampk Phosphorylation ◽  
Lymphoma Subtype

Abstract Abstract 4870 Since the succesful treatment of T cell lymphoma remains to be problematic, identification of new pharmacological targets in this malignancies are desperately needed. The AMPK-Rheb-mTOR signaling pathway plays an important role in regulating processes such as proliferation and proteinsynthesis according to energy and nutrient levels in normal and malignant T cells. Inhibitors of mTOR have shown promising results in clinical trials in several lymphoma types. Similarly, recent data could prove inhibitors of farnesyltransferase (FTI) to be effective as a single agent in certain subtypes of T cell lymphoma. Despite divergent data regarding the molecular target of FTI action, recently published work suggest inhibition of prenylation of the GTPase Rheb as putative mechanism for the antineoplastic effects of FTI (Basso et al., J Biol Chem, 2005). Therefore, combining inhibition of mTOR and Rheb might result in increased inhibition of T cell lymphoma proliferation. To investigate this hypothesis, human T cell lymphoma cell lines DERL-2 (originated from hepatosplenic gamma-delta T cell lymphoma), Karpas-299 (originated from anaplastic large cell T cell lymphoma) and normal human CD4+ T cells were incubated with a combination of everolimus as mTOR inhibitor and FTI (lonafarnib, SCH-66336) or the single agents. While both substances showed an additive combined anti-proliferative effect in DERL-2 cells, proliferation of Karpas cells were more susceptible to inhibition by FTI. On a molecular level, despite substantial growth inhibition in both cell lines by everolimus alone, phosphorylation of 4EBP1 and p70S6K remained unaffected, while FTI mediated reduction of Karpas cell proliferation was associated with a substantial decrease in AMPK phosphorylation together with an overexpression of p27kip, which could not be observed in DERL-2 cells. In contrast, incubation of stimulated human CD4+ T cells with the drugs alone or in combination did not result in changes in the phosporylation status of AMPK. Nevertheless, in contrast to everolimus, FTI induced a reduction of total protein expression of AMPK and other proteins, e.g. AKT. In addition, contrary to the observations in the malignant T cells, FTI treatment of unstimulated human CD4+ T cells resulted even in an increase of AMPK-phosphorylation. A hint for the explanation of these conflicting data came from analyses of Rheb expression in the examined cell types. While Rheb was easily detectable in the malignant T cell lines and the stimulated CD4+ T cells, it was almost absent in unstimulated CD4+ T cells. A model derived from this findings is that FTI effects depend on different targets available for inhibition of prenylation according to the activation or differentiation status of the T cells. While Rheb might be the target in malignant or activated T cells, another target, e.g. phosphatases, might be responsible for the FTI effect in resting T cells where Rheb is not available. In Karpas cells a particular connection between Rheb and AMPK might exist, as described for other cell lines (Lacher et al., Oncogene, 2010). Inhibition of this Rheb-AMPK axis might explain the particular gowth inhibiting effect of FTI in this model of anaplastic large T cell lymphoma. Nevertherless, the presented data show a combined effect of mTOR inhibitors and FTI for the potent treatment of T cell lymphoma involving different molecular mechanisms according to the lymphoma subtype. Disclosures: Finke: Fresenius Biotech GmbH: Honoraria, Research Funding.

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

Blood ◽  
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.

Utility of Interim and Post-Therapy PET/CT in T-Cell and NK-Cell Lymphoma: A Single Institutional Analysis over 9 Years

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3915-3915
Author(s):  
Kota Fukumoto ◽  
Manabu Fujisawa ◽  
Yasuhito Suehara ◽  
Yoshiaki Usui ◽  
Kentaro Narita ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Index Lesion ◽  
Pet Ct ◽  
Post Therapy ◽  
Initial Staging

Abstract Introduction: Positron emission tomography combined with computed tomography (PET-CT) is functional imaging test and has been widely used in malignant lymphoma (ML) for initial staging and monitoring response to treatment. Interim PET-CT (iPET) and post-therapy PET-CT (ePET) is also used to assess the early response and guide subsequent treatment, although its role is still controversial other than in Hodgkin's disease and diffuse large B cell lymphoma. Peripheral T cell lymphoma (PTCL) and natural killer (NK) cell lymphomas are relatively rare and heterogeneous types of ML. The prognosis of T and NK (T/NK) cell lymphoma is poor and no standard treatment is available. Therefore, there is a need to find better prognostic factors or tools for these patients. PET-CT is both sensitive and specific for initial staging of T/NK cell lymphoma, although there have been few studies using i- and ePET in these lymphomas. We investigated the prognostic value of i- and ePET in T/NK cell lymphoma in a retrospective single-center study. Methods: Between June 2006 and June 2015, 79 patients with T/NK cell lymphomas had iPET after 2 to 4 courses of treatment and at the end of treatment at Kameda Medical Center, Japan. iPET was performed just before the next cycle of treatment. Treatment responses were scored according to the Deauville score using a 5-point scale (DS). We defined DS scores 1 - 3 as complete metabolic response (CMR). Standardized uptake value (SUV) measurement was normalized relative to the injected dose and lean body mass. The SUV was measured for all lesions and the highest value for each scan was recorded as maximum SUV (SUVmax). These lesions were identified as indicator lesions. For mid- and end-treatment scans, we recorded the change in SUVmax (DSUV), comparing the index lesion and the highest SUVmax in the scan regardless of the index lesion. Differences in overall survival (OS) and progression-free survival (PFS) were calculated by two-sided log-rank test. PET-CT status was assessed for its ability to predict PFS and OS. Results: The study population consisted of 48 men and 31 women with a median age of 70 years. The most frequent lymphoma diagnoses were peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) (n  = 29), angioimmunoblastic T cell lymphoma (AITL) (n  = 21), anaplastic large cell lymphoma (ALCL) (n  = 6), adult T cell leukemia/lymphoma (ATLL) (n  = 12), enteropathy-associated T cell lymphoma (EATL) (n  = 2), and NK/T cell lymphoma (NKTCL) (n  = 9). Most patients except for ATLL and NK cell lymphoma were instituted with the CHOP-like regimen. Baseline PET scan was positive in all cases and median SUVmax was 13.7 (range, 2.6 - 37.4). iPET results were negative in 17 cases (26%), and ePET results were negative in 22 of 46 (48%) cases. With a median follow up of 30 months, 5-year PFS rate was 66% for obtaining CMR vs. 9.2% for not obtaining CMR (P  < 0.001). The percentages of patients that obtained CMR were 48% (14/29), 62% (13/21), 67% (4/6), 33% (3/9), 50% (1/2), and 56% (5/9) for those with PTCL-NOS, AITL, ALCL, ATLL, EATL, and NKTCL, respectively. The patients who obtained CMR showed significantly longer PFS and OS compared to those who did not. We also analyzed DSUVmax. Using the ROC curve, DSUVmax values between baseline and iPET of > 62% and > 85% were predictive of better PFS and OS (sensitivity 96%, specificity 67%, area under the curve (AUC) 0.89, 95% confidence interval (CI) = 0.82 - 0.97 and sensitivity 49%, specificity 97%, AUC 0.80, 95% CI = 0.70 - 0.90, respectively). We examined the positive and negative predictive values (PPV and NPV) and accuracy in predicting PFS and OS in 66 patients who underwent iPET. Of 35 iPET-positive patients, 31 (89%) showed progression, and 26 (74%) died during the follow-up. On multivariate Cox regression analysis, obtaining CMR at iPET emerged as an independent prognostic factor for PFS and OS (P<0.001 and P<0.001, respectively). Conclusions: Our data suggest that patients with positive results on i- or ePET should be considered candidates for intensive therapeutic strategies to improve their clinical outcome. Large prospective studies of patients with tumors of a homogeneous histological subtype within the T/NK cell lymphoma, treated with a uniform protocol, and evaluated on the basis of standardized criteria are warranted. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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