The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma

Savage, Kerry J.; Monti, Stefano; Kutok, Jeffery L.; Cattoretti, Giorgio; Neuberg, Donna; Leval, Laurence de; Kurtin, Paul J.; Cin, Paola Dal; Ladd, Christine; Feuerhake, Friedrich; Aguiar, Ricardo C.T.; Li, Sigui; Salles, Gilles; Berger, Françoise; Wen, Jing; Pinkus, Geraldine S.; Habermann, Thomas M.; Dalla‐Favera, Riccardo; Harris, Nancy L.; Aster, Jon C.; Golub, Todd R.; Shipp, Margaret A.

doi:10.1182/blood-2003-06-1841

Cited by 772 publications

(638 citation statements)

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“…Considering the former two entities, our data fit with previously reported frequencies in PMBCLs and cHL and are supported by data from gene expression profiling, pointing to the close relationship of these entities at the molecular level. 12,19,32,33 In cHL, the JAK2-STAT cascade is constitutively maintained at an active high level by multiple mechanisms, including stimulatory loops through interleukin (IL)-13 and its receptor IL13Ra1, gene dosage effect of the gained JAK2 locus at 9p24 in over 30% of cHL cases (present data) and aberrations of SOCS1. 19,21,34 These multiple mechanisms of JAK2-STAT activation in cHL point to its important oncogenic role.…”

Section: Discussionmentioning

confidence: 89%

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

et al. 2009

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The Janus kinase 2 (JAK2)-signal transducers and activators of transcription (STAT) pathway plays an important role in hematological malignancies. Mutations and translocations of the JAK2 gene, mapped at 9p24, lead to constitutive activation of JAK2 and its downstream targets. The presence of JAK2 mutations in lymphomas has been addressed in larger cohorts, but there are little systemic data on numerical and structural JAK2 aberrations in lymphoid neoplasms. To study the molecular epidemiology of these aberrations and the consecutive activation of the JAK2-STAT pathway in lymphomas, we examined 527 cases, covering the most common entities, in a tissue microarray by fluorescent in situ hybridization with breakable JAK2 probes, and immunohistochemistry for phosphorylated JAK2 (pJAK2) and its preferred downstream pSTAT3 and pSTAT5. 9p24 gains were detected in 6/17 (35%) primary mediastinal B-cell lymphomas (PMBCLs), 25/77 (33%) Hodgkin's lymphomas (HLs), 3/16 (19%) angioimmunoblastic T-cell lymphomas (AILTs) and 1/5 ALK1 þ anaplastic large cell lymphomas (ALCLs); breaks were observed only in three cases. pJAK2 expression was most prevalent in PMBCL, peripheral T-cell lymphomas and HL. pSTAT3 predominated in ALCLs, HLs, AILTs, PMBCLs and peripheral T-cell lymphomas. pSTAT5 expression was detected frequently in follicular lymphomas, diffuse large B-cell lymphomas and AILTs. 9p24 gains correlated with increased proportions of tumor cells expressing pJAK2 (P ¼ 0.002) and pSTAT3 (P ¼ 0.001). In follicular lymphomas, concomitant expression of pJAK2 and pSTAT5 was linked to better prognosis, whereas expression of pSTAT3 in nongerminal center-like diffuse large B-cell lymphomas could identify a patient group with an inferior outcome. Our findings stress that despite the rarity of activating JAK2 mutations in lymphomas, JAK2 is recurrently targeted by numerical, and rarely by structural, genetic aberrations in distinct lymphoma subtypes and that JAK2-STAT pathway may play a role in lymphomagenesis. Modern Pathology (2009) 22, 476-487; doi:10.1038/modpathol.2008; published online 9 January 2009 Keywords: Janus kinase 2; pSTAT3; pSTAT5; FISH; gains 9p24; lymphoma Genetic alterations of tyrosine kinases play an important oncogenic role. 1 The V617F and the less common K539L mutations of the Janus kinase 2 (JAK2) gene have been shown to be key pathogenic players in chronic myeloproliferative diseases. [2][3][4] Recently, translocations involving the JAK2 locus such as t(9;12)(p24;p23), t(8;9)(p24;q11.2), t(3;9) (q21;p24) and t(8;9)(p22;p24) were suggested to be of oncogenic importance in various hematological neoplasms, such as acute lymphoblastic and myelogenous leukemias, atypical chronic myeloid leukemias, myelodysplastic/myeloproliferative diseases and peripheral T-cell lymphomas. [5][6][7][8][9][10][11] Gains of JAK2 gene dosage, particularly due to trisomy 9p24, which is recurrent in classical Hodgkin's lymphoma

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Section: Discussionmentioning

confidence: 89%

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

et al. 2009

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“…13,14 Although additional subgroups within the germinal center diffuse large B-cell lymphomas based on the presence or absence of t(14;18)(q32;q21) have been defined, these did not predict survival. 15 Recently, an alternate approach, based on clustering of whole genome arrays has identified three new groups among diffuse large Bcell lymphomas: 'oxidative phosphorylation', 'B-cell receptor/proliferation', and 'host response', but these results were not associated with prognosis.…”

Section: Discussionmentioning

confidence: 99%

AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles

et al. 2006

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Based on gene expression profiling, diffuse large B-cell lymphomas arising in immunocompetent patients can be divided into germinal center and activated B-cell types. Since little is known about acquired immunodeficiency syndrome associated diffuse large B-cell lymphomas, we tested whether the protein expression of germinal center and activated B-cell markers differed between acquired immunodeficiency syndrome (AIDS) vs non-AIDS diffuse large B-cell lymphomas. We immunohistochemically stained tissue microarrays of 39 de novo diffuse large B-cell lymphomas: 12 AIDS associated and 27 non-AIDS, with germinal center (BCL6, CD10, CyclinH) and activated B-cell markers (MUM1, CD138, PAK1, CD44, BCL2). We scored each case for percent positive cells (0-19% ¼ 0; 20-49% ¼ 1; 50-100% ¼ 2). The activated B-cell and germinal center summation scores of each case were used as (x, y) coordinate data points to construct two-dimensional contour-frequency plots. The contour plot of non-AIDS diffuse large B-cell lymphomas showed two distinct clusters: a cluster with a high germinal center phenotype (cluster 1) and a cluster with a high activated B-cell phenotype (cluster 3). In contrast, the AIDS-related diffuse large B-cell lymphomas formed a single aggregate (cluster 2) (P ¼ 0.02, Fisher exact test). When the contour plots of the AIDS-related and the non-AIDS cases were superimposed, cluster 2 of the AIDS cases expressed an intermediate germinal center/activated B-cell phenotype compared to clusters 1 and 3 of the non-AIDS diffuse large B-cell lymphomas. Our results confirm that non-AIDS diffuse large B-cell lymphomas segregate into two groups with either germinal center or activated B-cell phenotype. We report the new finding that the AIDS status of the patient predicts the immunophenotype of the diffuse large B-cell lymphomas. We also describe a novel method for displaying immunohistochemical expression data using twodimensional contour-frequency plots. Materials and methods Lymphoma SamplesWe performed a retrospective study of 56 diffuse large B-cell lymphomas (23 AIDS-related and 33 non-AIDS) that were retrieved from the archives of

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“…Xiao et al (2004) detected nuclear REL staining in a high percentage (B85%) of Reed-Sternberg cells of classic HL. Nuclear REL staining has also been seen in the majority of 9 cases of Hodgkin's-like large cell lymphoma (Garcia et al, 2005), and in 5 of 6 and 7/7 cases of mediastinal large B-cell lymphoma (Savage et al, 2003;Feuerhake et al, 2005). Moreover, Rodig et al (2005) have recently presented data suggesting that nuclear REL staining and high level of expression of adaptor protein TRAF1, a possible REL target gene product, can be used to distinguish classical HL cells from other types of B-cell lymphomas, such as anaplastic large cell lymphoma, lymphocyte predominant HL, and nonmediastinal DLBCL.…”

Section: Multiple Familial Trichoepitheliomamentioning

confidence: 97%

Mutations in the NF-κB signaling pathway: implications for human disease

2006

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The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma

Cited by 772 publications

References 72 publications

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles

Mutations in the NF-κB signaling pathway: implications for human disease

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