Analyses of Pokemon Protein Expression in Lymphoma Reveals Elevated Expression in Nodular Lymphocyte Predominant Hodgkin Lymphoma Compared to Classical Hodgkin Lymphoma.

Abstract Background: POKEMON (for POK, Erythroid, Myeloid ONtogenic factor) has recently been shown to be a novel proto-oncogene, playing a key role in cellular transformation and repression of ARF. Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Because these transgenic mice developed T-cell lymphoma we sought to expand our original screening analyses. We intially showed POKEMON expression in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and co-expression of BCL6 and POKMEON showed higher proliferation and predicted for better overall survival in DLBCL (Nature 433, 278–285). Nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) is another tumor that expresses BCL6 and shows localization to L&H tumor cells. We therefore sought to compare POKEMON protein expression in NLPHL and Classical Hodgkin Lymphoma (cHL) cases. Design: Stains for POKEMON were performed with the anti-POKEMON hamster monoclonal antibody (clone 13E9). Sections of reactive human tonsil were stained as controls showing localization to squamous epithelium and reactive germinal centers as well as paracortical regions. For NLPHL, the cohort comprised of 19 males, 2 females; for cHL 16 males, 14 females. 20 NLPHL and 30 cHL tissue biopsies were stained using whole sections. Intensity and percent positivity of malignant L&H cells and Reed-Sternberg (RS) cells as well as surrounding reactive lymphocytes was scored. Expression in T-cell lymphomas was expanded to include a total of 84 cases analyzed by tissue microarray (TMA) that included: 8 ALCL (Anaplastic Large Cell Lymphoma), 11 AILT (Angioimmunoblastic T-cell Lymphoma), 17 T-ALL (T Lymphoblastic Lymphoma), 43 PTCL (Peripheral T-cell Lymphoma), 3 T/NK (Nasal type T/NK cell Lymphoma), and 2 PTCL, NOS (Not Otherwise Subclassified). Tumor cells in T-cell lymphomas and HL were scored and defined as 0 (negative), 1 (scattered <50%, weak positive), and 2 (diffuse >50%, strong positive) with a nuclear localization pattern. Results: For NLPHL, 18/20 (90%) cases showed diffuse strong positivity in >50% of malignant L&H tumor cells whereas in cHL cases, 6/30 (20%) cases showed diffuse strong positivity in >50% of malignant RS tumor cells for POKEMON protein expression. In T-cell lymphomas, POKEMON expression was strongest in ALCL (6/8, 75%) and AILD (7/11, 74%) compared to the other subtypes. In contrast, BCL6 protein expression was positive in 12/20 (60%) cases which showed weak, scattered to diffuse strong positivity in L&H tumor cells and 1/30 (3%) with scattered weak reactivity in cHL malignant RS cells Conclusion: POKEMON is co-expressed with BCL6 in malignant L&H tumor cells in NLPHL but not in cHL. Pokemon’s critical role in cellular transformation makes it an attractive target for therapeutic intervention in NLPHL.

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Classical Hodgkin Lymphoma With Aberrant CD8 Expression: A Clinicopathologic Study of Five Cases

International Journal of Surgical Pathology ◽

10.1177/1066896918790384 ◽

2018 ◽

Vol 27 (2) ◽

pp. 166-173

Author(s):

Neda Mirzamani ◽

Xinmin Zhang ◽

Judith Brody ◽

Silvia G. Spitzer ◽

Filiz Sen ◽

...

Keyword(s):

T Cell ◽

Hodgkin Lymphoma ◽

Tumor Cells ◽

T Cell Receptor ◽

Cell Lymphoma ◽

Cell Receptor ◽

T Cell Lymphoma ◽

Classical Hodgkin Lymphoma ◽

Peripheral T Cell Lymphoma ◽

T Cell Receptor Genes

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (CHL) are of B-cell origin. In a small number of CHL cases, the tumor cells can express T-cell antigens. CD8 expression in this setting is extremely rare. We identified 5 cases of CHL with aberrant CD8 expression from our database. The patients included 3 men and 2 women with a median age of 33 years (range = 20-59 years). All the patients initially presented with lymphadenopathy and variable number of RS cells. Two cases were classified as mixed cellularity type that showed prominent vascular proliferation mimicking peripheral T-cell lymphoma. Two cases represented nodular sclerosis type. The tumor cells in all cases were positive for CD8 and negative for CD2, CD3, CD4, and CD7 and carried germline T-cell receptor genes. Molecular studies revealed T-cell receptor genes to be in germline configuration in 4 cases with available information. Given the morphologic overlap with peripheral T-cell lymphoma and the rarity of this type of CHL, identifying more cases will help our better understanding of this entity.

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Differential Expression of the Homeobox Gene MIXL1 in Non Hodgkin (NHL) and Hodgkin Lymphomas (HL).

Blood ◽

10.1182/blood.v106.11.3014.3014 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3014-3014

Author(s):

Elias Drakos ◽

George Z. Rassidakis ◽

Wei Guo ◽

L. Jeffrey Medeiros ◽

Lalitha Nagarajan

Keyword(s):

T Cell ◽

Protein Expression ◽

B Cell ◽

Tumor Cells ◽

Cell Lymphoma ◽

Lymphoblastic Leukemia ◽

T Cell Lymphoma ◽

High Grade ◽

Intermediate Grade ◽

Aberrant Expression

Abstract The gene MIXL1 (Mix1 homeobox-like) encodes a paired class homeobox transcription factor involved in early hematopoietic specification during embryogenesis. Previous studies have shown that MIXL1 gene is expressed in hematopoietic cells during adult life (Guo et al. Blood100;1;89–96, 2002). Furthermore 5′ MIXL1 sequences are a target of retroviral insertion in murine T-cell lymphoma (http:RTCGD.ncifcrf.gov), suggesting a selection advantage for aberrant expression of this gene. However, the status of MIXL1 expression in human lymphomas has not been examined. Using a highly specific antibody, we assessed for MIXL1 protein expression in 14 lymphoma cell lines (9 B-cell and 5 T-cell) by immunobloting. MIXL1 was detected predominantly in nuclear extracts of lysates of all cell lines tested, although at a variable level. We also assessed for MIXL1 protein expression in 126 B-cell and 21 T-cell NHLs of various types, as well as 14 Hodgkin lymphomas using immunohistochemical methods. The results of the immunohistochemical studies are summarized in table 1. Once again, MIXL1 immunoreactivity was primarily nuclear in the tumor cells. Based on distribution data (histogram), a 50% cutoff was selected for high versus low MIXL1 expression. Among B-cell tumors, high expression levels of MIXL1 protein were more frequently detected in high-grade NHL and HL compared with low/intermediate grade NHL (p<0.0001, chi-square test). As a continuous variable, the percentage of MIXL1-positive tumor cells was also significantly higher in high-grade B-cell NHL and HL compared with low/intermediate grade NHL (p<0.0001, Kruskal Wallis test). All Hodgkin lymphomas expressed high levels of MIXL1 with 60% to 100% of neoplastic cells being positive for MIXL1. Most T-cell NHLs also expressed high levels of MIXL1. In contrast, most low/intermediate-grade B-cell NHL and multiple myelomas expressed low levels of MIXL1. Frequent overexpression of MIXL1 gene product in most high-grade B-cell NHLs, HL and T-cell NHLs suggests that aberrant expression of MIXL1 may play a role in proliferation, block of differentiation or both. Table 1. HL (n=14) B-NHL (n =126) T-NHL (n =21) N (%) Low/intermediate grade N (%) N (%) Classical HL 12/12(100%) Chronic lymphocytic leukemia /small lymphocytic lymphoma 0/8 (0% T-precursor lymphoblastic leukemia/lymphoma 2/2 (0%) Nodular lymphocyte predominance HL 2/2 (100%) MALT-lymphoma 0/8 (0%) Mycosis fungoides/Sezary syndrome 2/2 (0%) Follicular lymphoma 9/24 (38%) Extranodal NK/T-cell lymphoma, nasal type 3/3 (100%) Mantle cell lymphoma 5/34 (15%) Peripheral T-cell lymphoma, unspecified 6/9 (66% High grade Anaplastic large cell lymphoma 5/5 (100%) B-precursor lymphoblastic leukemia/lymphoma 1/3 (33%) Burkitt lymphoma/leukemia 2/2 (100%) Diffuse large B-cell lymphoma 30/31 (97%) Plasma cell myeloma/plasmacytoma 0/16 (0%)

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Clinical Applications of the Genomic Landscape of Aggressive Non-Hodgkin Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.7603 ◽

2017 ◽

Vol 35 (9) ◽

pp. 955-962 ◽

Cited By ~ 25

Author(s):

Andrea B. Moffitt ◽

Sandeep S. Dave

Keyword(s):

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large Cell ◽

T Cell Lymphoma ◽

Adult T Cell Leukemia ◽

Non Hodgkin Lymphoma ◽

T Cell Lymphomas

In this review, we examine the genomic landscapes of lymphomas that arise from B, T, and natural killer cells. Lymphomas represent a striking spectrum of clinical behaviors. Although some lymphomas are curable with standard therapy, the majority of the affected patients succumb to their disease. Here, the genetic underpinnings of these heterogeneous entities are reviewed. We consider B-cell lymphomas, including Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, and primary mediastinal B-cell lymphoma. We also examine T-cell lymphomas, including anaplastic large-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma, and other peripheral T-cell lymphomas. Together, these malignancies make up most lymphomas diagnosed around the world. Genomic technologies, including microarrays and next-generation sequencing, have enabled a better understanding of the molecular underpinnings of these cancers. We describe the broad genomics findings that characterize these lymphoma types and discuss new therapeutic opportunities that arise from these findings.

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Nodal Involvement by Cutaneous CD30-positive T-cell Lymphoma Mimicking Classical Hodgkin Lymphoma

The American Journal of Surgical Pathology ◽

10.1097/pas.0b013e3182487158 ◽

2012 ◽

Vol 36 (5) ◽

pp. 716-725 ◽

Cited By ~ 40

Author(s):

Franziska C. Eberle ◽

Joo Y. Song ◽

Liqiang Xi ◽

Mark Raffeld ◽

Nancy Lee Harris ◽

...

Keyword(s):

T Cell ◽

Hodgkin Lymphoma ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Classical Hodgkin Lymphoma ◽

Nodal Involvement

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Impact of Growth Factor Independence 1 in Human T-Cell Lymphomas; Pathogenic Potential Identified by Insertional Mutagenesis in a Murine T-Cell Lymphoma Model.

Blood ◽

10.1182/blood.v114.22.5047.5047 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5047-5047

Author(s):

Magdalena Julia Dabrowska ◽

Karen Dybkaer ◽

Preben Johansen ◽

Hans Erik Johnsen ◽

Finn Skou Pedersen

Keyword(s):

T Cell ◽

Protein Expression ◽

Posttranscriptional Regulation ◽

Immunohistochemical Staining ◽

Insertional Mutagenesis ◽

Cell Lymphoma ◽

Expression Patterns ◽

T Cell Lymphoma ◽

T Cell Lymphomas ◽

Human T Cell

Abstract Abstract 5047 Introduction The transcriptional repressor and oncogene Growth factor independence 1 (Gfi1) has a major oncogenic potential and is aberrantly expressed in murine lymphomas and several human cancers. Gfi1 is a key regulator of stem cell quiescence and plays a significant role in T-cell development, lineage commitment, and influences development of maturate granulocytes and monocytes. The genomic locus on murine chromosome 5 encoding Gfi1 is a frequent integration locus activated in T-cell lymphomas induced by the SL3-3 Murine Leukemia Virus (MLV) as well as other MLVs, indicating that Gfi1 is essential in development of these tumors. In the SL3-3 induced T-cell lymphoma model, retroviral insertions in the Gfi1 3'UTR have been demonstrated to decouple microRNA-mediated posttranscriptional regulation of protein expression (Dabrowska et al, 2009) further supporting its role in lymphomagenesis. In human cancers, Gfi1 protein expression has been observed in HTLV-1 induced ATLL and SCLC but no knowledge exists on how Gfi1 contributes to initiating and maintaining human T-cell lymphomas. Methods Gfi1 gene and protein expression patterns were determined in precursor and mature human T-cell lymphomas by real time PCR and Western blot analysis. Furthermore, localization and expression patterns of the Gfi1 protein was determined in the human T-cell lymphomas by immunohistochemical staining with Gfi1 antibodies and compared to similar staining of MLV induced tumors. Results Our results demonstrated that Gfi1 mRNA and protein levels vary significantly among the human T-cell lymphomas, and do not always show a direct proportional pattern. Thus, Gfi1 mRNA expression can be relatively high without resulting in a corresponding high protein expression, suggesting that a microRNA mediated posttranscriptional regulation exists in some tumors but may be disrupted in others. Furthermore, an additional Gfi1 protein variant was identified in one of the T-cell lymphoma entities. Immunohistochemical staining demonstrated varying Gfi1 protein expression in both nucleus and cytoplasm in the T-cell lymphomas and different distributions of the protein within the tumor and tumor cells were observed among samples. Staining of normal human tonsil demonstrated Gfi1 protein to be localized in the cytoplasm. We hypothesise that regulation of Gfi1 may include shuttling between cytoplasm and nucleus and that lymphomagenesis enables unlimited nuclear access. Conclusion Our data shows that deregulated Gfi1 expression plays a major role in the development of MLV induced lymphomas and strongly indicates that retroviral insertional mutagenesis in murine models of human NHLs can be used to identify new genes involved in lymphomagenesis and, by use of functional assays, their impact on human lymphomas can be evaluated. Disclosures No relevant conflicts of interest to declare.

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