In-Vivo Activation Of STAT3 In Angioimmunoblastic T Cell Lymphoma, PTCL Not Otherwise Specified, and ALK Negative Anaplastic Large Cell Lymphoma: Implications For Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 844-844 ◽  
Author(s):  
Mamta Gupta ◽  
Matthew J. Maurer ◽  
Mary Stenson ◽  
Linda E. Wellik ◽  
Jing Jing Han ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Large Cell Lymphoma ◽  
High Level ◽  
Very High

Abstract T cell lymphoma (TCL) is a heterogeneous group of malignant lymphomas and is subdivided in three major subgroups, (i) cutaneous (mycosis fungoides (MF), sezary syndrome (SS) and primary CTCL), (ii) nodal (peripheral T-cell lymphoma, PTCL NOS, anaplastic large cell lymphoma (ALCL), angioimmunoblastic (AITL)) (iii) and extranodal. Because of this broad morphological spectrum and immunophenotypic variation the pathogenesis of most of the TCL is poorly understood. Constitutive STAT3 signaling provides growth-promoting signals in many forms of malignancy; however in-vivo activation of phosphorylated STAT3 and its clinical correlation in subtypes of TCLs has not been extensively studied. In this study we examined constitutive STAT3 activation in various subtypes of TCL tumors and performed pre-clinical testing to determine whether STAT3 inhibitors will be effective. First, we assessed the STAT3 activation (pSTAT3Tyr705) by immunohistochemistry (IHC) on a tissue microarray (TMA) from 169 untreated TCL patient samples. Using a cutoff of ≥30% pSTAT3 nuclear staining, 38% (64/169) of TCL tumors were pSTAT3+. Interestingly, pSTAT3 was differentially expressed among the various TCL subgroups. 27% (16/59) PTCL NOS, 29% (11/38) AITL, 93% (14/15) ALK+ ALCL, 57% (13/28) ALK- ALCL, 50% (6/12) extranodal NK/T cell tumors and 17% (1/6) primary cutaneous showed pSTAT3 positivity. Using either a 30% or 80% cut-off, pSTAT3 positivity was associated with inferior event free survival for AITL, PTCL NOS and ALK neg ALCLs TCLs. Due to small sample size within each group statistical significance (p=0.03) was met only for ALK neg ALCL (80% cutoff). Further analysis in the human TCL cell lines and normal control T-cells also revealed differential expression of pSTATs. ALCL cell lines, Karpas 299 and SR786 were pSTAT3 positive but pSTAT5 negative. Both the CTCL (SS) cell lines HuT78 and SeAx were pSTAT3 negative, however MyLa a cell line of MF origin was strongly pSTAT3+ and pSTAT5+. The normal control CD4 T-cells was pSTAT3- and pSTAT5+. These data clearly suggest that pSTAT3 is differentially expressed among the TCL tumors and is a potential therapeutic target. Potential mechanisms for STAT3 activation could be aberrant secretion of cytokines/chemokines produced by the tumor itself or the tumor microenvironment. We compared the cytokine profile of the culture supernatant from pSTAT3 positive SUDHL1 and pSTAT3 negative HuT78 TCL cell lines using a 30-plex ELISA. The most significantly different cytokines among these 2 cell lines were interleukin -10 (IL-10) and soluble interleukin-2 receptor alpha (sIL-2Ra). The SUDHL1 was found to secrete a very high level (1700 pg/ml) of IL-10, in contrast to only 167 pg/mL in the HuT78 supernatant. Moreover, SUDHL1 secretes 3.5 times more sIL-2Ra (6600 pg/ml) than the pSTAT3 negative cell line HuT78 (1800 pg/ml). In-vitro exposure to IL-10 but not sIL-2Ra was able to further upregulate pSTAT3 in SUDHL1 and Karpas 299. Overall, these data suggest that autocrine secretion of IL-10 but not sIL-2Ra is important for STAT3 activation in ALCL TCLs. Next we compared the cytokine profile of 2 pSTAT3 positive cells from different origin; SUDHL1 (ALCL) and MyLa (MF). In contrast to SUDHL1 (which produce high level of IL-10), MyLa was producing very little IL-10 (18pg/ml). The other most significantly different cytokines between these cells was RANTES with MyLa producing a very high level (28897 pg/ml) and SUDHL1 a very low level (8pg/ml). We also noticed differential level of IL-13 between these cells; MyLa producing 113pg/ml while SUDHL1 only 13 pg/ml. SAR302 (Sanofi, Cambridge, MA), a selective JAK2 inhibitor currently in clinical trial for myeloproliferative neoplasms was able to inhibit autocrine secretion of IL-10 but not sIL-2Ra in a dose-dependent manner followed by STAT3 dephosphorylation and decreased lymphoma cell survival. In summary, our data provide first evidence of in-vivo STAT3 activation in AITL, PTCL NOS, ALK negative ALCL TCLs using TMA from patient samples. Comprehensive cytokine analysis determined IL-10 as an autocrine factor driving STAT3 activation in ALCLTCLs, while RANTES and IL-13 might be important drivers for STAT3 activation in MF TCLs. Finally our data provide a mechanistic basis of selecting and targeting TCL tumor cells with high IL-10 levels and/or constitutive STAT3 activity with potent and novel JAK2 inhibitors such as SAR302 or other STAT3 inhibitors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clonotype pattern in T-cell lymphomas map the cell of origin to immature lymphoid precursors

2021 ◽  
Author(s):  
Aishwarya Iyer ◽  
Dylan Hennessey ◽  
Robert Gniadecki
Keyword(s):  
T Cells ◽  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Cell Of Origin ◽  
Peripheral T Cell Lymphoma ◽  
T Cell Lymphomas ◽  
Large Cell Lymphoma

Background Mature T-cell lymphomas (TCLs) are rare, clinically heterogeneous hematologic cancers of high medical need. TCLs have inferior prognosis compared with their B-cell counterparts, which is attributed to poor understanding of their pathogenesis. Based on phenotypic similarities between normal and neoplastic lymphocytes it has been assumed that TCLs develop in the periphery, directly from various subtypes of normal T-cells. Methods and findings To address the debated question of the cell of origin in TCLs we analyzed to identify the highly variable complementarity determining regions (CDR3) regions of T-cell receptor (TCR) to trace the clonal history of the T-cells. We have collected previously published whole genome -exome, and -transcriptome sequencing data from 574 TCL patients comprising five nodal lymphomas [anaplastic large cell lymphoma (n=67), peripheral T-cell lymphoma (PTCL, n=55), adult T-cell lymphoma/leukemia (n=135), natural killer T-cell lymphoma (NKCL, n=25), not specified/other (n=30)] and three extranodal, cutaneous T-cell lymphomas [mycosis fungoides (n=122), Sezary syndrome (n=130), and subcutaneous panniculitis like T-cell lymphoma (n=10)]. TCR clonotypes contained in the tumor cell fraction, representing the clonotypes of malignant cells, were identified by de novo assembly of CDR3 regions of TCRγ, β and α. We have found that the vast majority of TCLs are clonotypically oligoclonal, although the pattern oligoclonality varied. Anaplastic large cell lymphoma was most diverse comprising multiple clonotypes of TCRγ, β and α whereas adult T-cell lymphoma/leukemia and peripheral T-cell lymphomas often showed monoclonality for TCRγ and β but had diverse TCRα clonotypes. These patterns of rearrangements were not compatible with the current mature T-cell precursor model and indicated that TCLs are initiated at the level of the lymphoid precursor. In keeping with this hypothesis, TCR rearrangements in TCLs resembled the pattern seen in the human thymus showing biased usage of V and J segments of high combinatorial probability resulting in recurrent, public CDR3 sequences shared between unrelated patients and across different clinical TCL entities. Frequencies of malignant clonotypes followed Zipf-Mandelbrot scaling law suggesting that TCLs comprise an interconnected system of expanding tumor clones. The major limitation of this study is that it is based on the analysis of the TCR clonotypes and does not directly inform about developmental trajectories of cellular clones. Conclusions Lymphoid precursors are the likely cells of origin for mature T-cell lymphomas. Anaplastic large cell lymphoma seems to be derived from the most immature precursors with germline TCR whereas peripheral T-cell lymphoma and adult T-cell lymphoma/leukemia map to the later stages after TCR lower case Greek beta rearrangement stage. Clonotypically diverse initiating cells may seed target tissues being responsible for disease relapses after therapy.

Spectrum of Expression and Biological Activity of Programmed Death Ligand 1 (PD-L1) in Non-Hodgkin’s Lymphomas

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4140-4140
Author(s):  
David J Andorsky ◽  
Reiko Yamada ◽  
Kristopher K Steward ◽  
Sven De Vos ◽  
Jonathan Said ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Grey Zone ◽  
Programmed Death ◽  
Mantle Cell ◽  
Large Cell Lymphoma

Abstract Programmed Death Ligand 1 (PD-L1) is expressed on antigen presenting cells and serves to inhibit activation of T cells through its receptor, Programmed Death 1 (PD-1). PD-L1 is aberrantly expressed on epithelial malignancies and may prevent an effective host antitumor immune response. However, the pattern of expression and function of PD-L1 in non-Hodgkin lymphoma (NHL) is largely unknown. We examined 77 primary NHL tissue specimens and 16 NHL cell lines for expression of PD-L1. PD-L1 was detected by immunohistochemical staining in all 14 anaplastic large cell lymphoma (ALCL) specimens (both ALK+ and ALK-), and in 18 of 22 diffuse large B cell lymphomas (DLBCL). PD-L1 was expressed in all cases of Hodgkin’s, mediastinal B cell, and grey zone lymphoma, 50% of peripheral T cell lymphomas, 15% of follicular lymphomas, and 33% of mantle cell lymphomas. Among DLBCL cases subtyped into germinal-center B (GCB) and non-GCB using CD10, BCL-6, and MUM-1 (Hans et al, Blood2004;103:275), 8 of 12 (66%) GCB cases expressed PD-L1, compared to 10 of 11 (91%) of non-GCB cases (p=0.31). Among NHL cell lines, all 9 B cell lines were negative for PD-L1, as measured by flow cytometry, but all 5 ALCL cell lines were strongly positive. Therefore, we chose to focus on ALCL to study the role of PD-L1 in modulating anti-lymphoma T cell activity. PD-L1 expressed by ALCL was biologically active in that proliferation of allogeneic T cells co-cultured with Karpas 299 ALCL cells was significantly enhanced by blocking PD-L1 with monoclonal antibodies. To further study tumor-T cell interactions, malignant ascites from a patient with newly diagnosed ALK+ ALCL, containing approximately equivalent proportions of PD-L1-expressing tumor cells and tumor-associated T cells, was used as an autologous system. Secretion of interferon-γ after 3- or 5-day incubation of the T cell/tumor mixture with phytohemagglutinin (a polyclonal T cell activator) was increased four-fold in the presence of anti-PD-L1 antibody, as compared with control antibody or media alone. Secretion of other inflammatory cytokines, including IL-1, TNFα, IL-5, IL-13, and MIP1α, was also markedly increased with the addition of anti-PD-L1 antibody to the mixture of tumor cells and lymphocytes. In conclusion, PD-L1 is expressed in a broad array of non-Hodgkin lymphomas, particularly in ALCL. Blockade of tumor-associated PD-L1 promoted activation of adjacent T cells. PD-L1 may play a role in thwarting an effective antitumor immune response, and thus represents an attractive target for lymphoma immunotherapy using anti-PD-L1 or anti-PD-1 monoclonal antibodies. Heterogeneity of PD-L1 expression among DLBCLs may be related to GCB subtype or other biological properties, and these associations are being explored in a larger set of DLBCL cases. Table 1. PD-L1 expression by lymphoma subtype. Subtype Number PD-L1+ % Anaplastic large cell lymphoma 14 14 100% Diffuse large B cell lymphoma 22 18 82% T cell rich DLBCL 7 4 57% Follicular lymphoma 13 2 15% Mantle cell lymphoma 6 2 33% Mediastinal DLBCL 2 2 100% Hodgkin lymphoma 5 5 100% Grey zone lymphoma 1 1 100% Peripheral T cell lymphoma 7 4 57%

scholarly journals A Novel Antibody Drug Conjugate (ADC) Targeting Cell Surface Heat Shock Protein 70 (csHSP70) Is Active Against Pre-Clinical Models of Peripheral T-Cell Lymphoma (PTCL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 870-870
Author(s):  
Rajan Kumar Choudhary ◽  
Richard J. Jones ◽  
Isere Kuiatse ◽  
Hua Wang ◽  
Francisco Vega ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Rna Seq

Abstract Background: Neoplasms of T-cell or natural killer/T-cell origin account for 10-15% of all non-Hodgkin lymphomas (NHLs) in the United States, and 30% or more of NHLs in African and Asian countries, and tumors from post-thymic or peripheral T-cells are referred to collectively as PTCLs. Recent advances, including approval of brentuximab vedotin (BV), an anti-CD30 monoclonal antibody (mAb) drug conjugate (ADC) with monomethyl auristatin E (MMAE), deacetylase inhibitors (HDACis), and Anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive anaplastic large cell lymphoma (ALCL) have improved outcomes. However, most PTCLs still have a poorer prognosis than comparable B-cell NHLs, and identification of novel targets and drugs retains importance in this area of unmet medical need. Methods: Pre-clinical studies were performed using PTCL and cutaneous T-cell lymphoma (CTCL) cell lines initially in vitro, and then using an in vivo xenograft model. Publically available databases were also leveraged, including the Broad Institute Cancer Cell Line Encyclopedia (CCLE), as well as our own RNA-sequencing (RNA-Seq) data from primary PTCL samples. Results: We examined the cell surface proteome of SUD-HL-1 (ALK+ ALCL), Mac-1 (ALK- ALCL), HH (CTCL), and HuT 78 (Mycosis fungoides with Sézary syndrome) cells by biotinylation and then mass spectrometry, and identified csHSP70 as being consistently expressed in all four lines. Analysis of the CCLE showed that HSP70 mRNA and HSP70 protein was expressed at the highest level in T-cell lymphoma cell lines, and our own RNA-Seq data confirmed HSP70 gene expression was higher in primary PTCL samples, and especially in ALCLs, compared with normal T-cells. To test its promise as a therapeutic target, we generated mAbs to human HSP70 and identified one clone, 239-87, which specifically bound csHSP70 on T-cell NHL cell lines but not on normal peripheral blood-derived mononuclear cells (PBMCs). Next, 239-87 was linked to MMAE to generate an ADC with a drug:antibody ratio of 4, and we confirmed that it was both internalized and then trafficked into acidic vacuoles in SUD-HL-1 cells. The 239-87-MMAE ADC induced a time- and concentration-dependent loss of viability in a panel of PTCL and CTCL cell lines associated with a G2/M arrest and induction of apoptosis, while normal PBMCs were unaffected. Comparisons of the activity of BV with 239-87-MMAE showed that the latter had similar efficacy against SU-DHL-1 and Hut 78 cells in vitro. When cells were propagated under conditions of hypoxia to mimic the tumor microenvironment there was an increase in csHSP70 expression, and the sensitivity of PTCL and CTCL cell lines to the 239-87-MMAE ADC was enhanced. Conversely, an inducible HSP70-targeted short hairpin RNA reduced total and csHSP70 protein expression, and reduced the efficacy of the ADC. Also of note, the HDACi vorinostat enhanced csHSP70 levels, and combinations of vorinostat with the 239-87-MMAE ADC enhanced loss of viability in these cells in a synergistic manner based on combination index analyses. Finally, we prepared an orthotopic in vivo PTCL model by subcutaneously injecting luciferase-labeled Mac-1 cells into C.B-17/IcrHsd-Prkdc scid mice. Disease progression occurred rapidly in all mice treated once weekly on days 10, 17, 24, and 31 with an IgG2A isotype mAb, as was the case for 7/8 mice treated with the 239-87-MMAE ADC at 1 mg/kg. In contrast, palpable tumor disappeared in 1/8 mice that received this ADC at 1 mg/kg, and 8/8 and 7/7 mice that received dosing at 5 and 10 mg/kg, respectively (Figure 1A). Tumor recurrence has not been seen at 105 days, including 74 days since the last ADC dose, and the one mouse at 1 mg/kg, and 3 each in the 5 and 10 mg/kg cohorts have had no disease by imaging, while the others have a small residual signal (Figure 1B) that has not progressed for two months. Conclusions: These pre-clinical in vitro and in vivo data support the possibility that csHSP70 could represent a novel therapeutic target for PTCL, and provide a rationale to translate ADCs based on our clone 239-87 mAb to the clinic for patients with advanced ALCL, and potentially other T-cell lymphomas as well. Figure 1 Figure 1. Disclosures Jones: Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company. Vega: i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding; CRISPR Therapeutics and Geron: Research Funding. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees.

The Role of IgM Antibodies in T Cell Lymphoma Protection in a Novel Model Resembling Anaplastic Large Cell Lymphoma

2021 ◽  
pp. ji2001279
Author(s):  
Chuancang Jiang ◽  
Ming-Lang Zhao ◽  
Luis Ramos ◽  
Katarzyna Dobaczewska ◽  
Ronald Herbert ◽  
...  
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Igm Antibodies ◽  
Large Cell Lymphoma ◽  
Novel Model

The T-Cell Activation Markers CD30 and OX40/CD134 Are Expressed in Nonoverlapping Subsets of Peripheral T-Cell Lymphoma

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3487-3493 ◽  
Author(s):  
Dan Jones ◽  
Christopher D.M. Fletcher ◽  
Karen Pulford ◽  
Aliakbar Shahsafaei ◽  
David M. Dorfman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Tnf Receptor ◽  
T Cell Lymphomas ◽  
Tumor Types ◽  
Tnf Receptor Family ◽  
Receptor Family

The tumor necrosis factor (TNF) receptor family includes several important markers of activation in T cells. We examined expression patterns of two T-cell-associated members of these receptors, namely CD30 and OX40/CD134, in 148 cases of T-cell lymphoma to identify possible objective immunohistochemical criteria for subclassification of these tumors. CD30 expression was characteristic of tumors with an anaplastic (46/47 cases [98%]) or large-cell (10/21 [48%]) morphology and was seen in only scattered cells in other tumor types. In contrast, large numbers of OX40/CD134+ tumors cells were typical of angioimmunoblastic lymphoma (15/16 [94%]), angiocentric lymphoma (4/4), a subset of large-cell lymphomas (10/21 [48%]), and lymphomas with a prominent histiocytic component (6/7 [86%]). Strong OX40/CD134 and CD30 coexpression was seen in only 4% of tumors, typically those with an anaplastic/Hodgkin’s-like appearance. OX40/CD134 expression was characteristic of tumors composed of activated CD4+ T cells and was not seen in small-cell T-cell lymphomas, lymphoblastic lymphomas, or other tumor types, including B-cell lymphomas or carcinomas. These results suggest that immunostaining for OX40/CD134 may be helpful in subclassification of peripheral T-cell lymphomas and that the patterns of TNF receptor family expression in these tumors may parallel those seen within nonneoplastic helper T-cell subsets.

Cytologic transformation in cutaneous T cell lymphoma: a clinicopathologic entity associated with poor prognosis.

1987 ◽  
Vol 5 (2) ◽  
pp. 208-215 ◽  
Author(s):  
E Dmitrovsky ◽  
M J Matthews ◽  
P A Bunn ◽  
G P Schechter ◽  
R W Makuch ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Blood Smears ◽  
Large Cell Lymphoma ◽  
Aggressive Clinical Course ◽  
Peripheral Blood Smears

The clinical course of cutaneous T cell lymphoma (mycosis fungoides and Sezary syndrome) is generally indolent, but in occasional patients becomes fulminant. We found that biopsies from patients with accelerating disease can reveal cytologic transformation from previously observed small, convoluted lymphocytes to large cells that are similar to cells seen in large-cell lymphoma. The cerebriform nuclei characteristic of malignant T cells can only rarely be identified. Of 150 cutaneous T cell lymphoma patients we treated from 1976 to 1984, cytologic transformation was identified in 12 after review of peripheral blood smears and biopsies from skin, lymph nodes, and visceral sites. Patients who developed cytologic transformation were initially characterized by advanced stage (11 of 12), with lymph node effacement (seven of 11) and erythroderma (five of 12). The tumor cell DNA content after transformation was aneuploid (four of four), and the ability to form rosettes with sheep erythrocytes was retained in transformed cells (three of three). The median time from diagnosis of cutaneous T cell lymphoma to cytologic transformation was 21.5 months (range, 4 to 64), and the median survival from transformation was only 2 months (range, 0 to 19+). We conclude that cytologic transformation in cutaneous T cell lymphoma represents a distinct clinicopathologic entity, characterized by an aggressive clinical course.

scholarly journals IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 360-370 ◽  
Author(s):  
Ping Shi ◽  
Raymond Lai ◽  
Quan Lin ◽  
Abid S. Iqbal ◽  
Leah C. Young ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Malignant Lymphoma ◽  
Cell Lines ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Type I ◽  
Large Cell Lymphoma

Abstract Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase plays important roles in the pathogenesis of several malignancies. Although it promotes the growth of stimulated hematopoietic cells, a direct role of IGF-IR in malignant lymphoma has not been identified. Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+ ALCL) is a unique type of T-cell lymphoma. Approximately 85% of ALK+ ALCL cases harbor the translocation t(2;5)(p23;q35), which generates the chimeric oncogene NPM-ALK. In the present study, we explored a possible role of IGF-IR in ALK+ ALCL. Our results demonstrate that IGF-IR and IGF-I are widely expressed in ALK+ ALCL cell lines and primary tumors. Importantly, we identified novel reciprocal functional interactions between IGF-IR and NPM-ALK. Antagonism of IGF-IR decreased the viability, induced apoptosis and cell-cycle arrest, and decreased proliferation and colony formation of ALK+ ALCL cell lines. These effects could be explained by alterations of cell survival regulatory proteins downstream of IGF-IR signaling. Our findings improve current understanding of the biology of IGF-IR and NPM-ALK and have significant therapeutic implications as they identify IGF-IR signaling as a potential therapeutic target in ALK+ ALCL and possibly other types of malignant lymphoma.

ALK-negative anaplastic large-cell lymphoma demonstrates similar poor prognosis to peripheral T-cell lymphoma, unspecified

2003 ◽  
Vol 43 (5) ◽  
pp. 462-469 ◽  
Author(s):  
R L ten Berge ◽  
P C de Bruin ◽  
J J Oudejans ◽  
G J Ossenkoppele ◽  
P van der Valk ◽  
...  
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Poor Prognosis ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Large Cell Lymphoma
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