Lack and/or aberrant localization of major histocompatibility class II (MHCII) protein in plasmablastic lymphoma

Schmelz, Monika; Montes‐Moreno, Santiago; Piris, Miguel Á.; Wilkinson, Sarah T.; Rimsza, Lisa M.

doi:10.3324/haematol.2011.060186

Cited by 13 publications

(7 citation statements)

References 7 publications

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“…Consistent with previously published data, 9 MHCII protein/ HLA (DP, DR) was virtually absent in PBL. Only three cases out of 25 tested were positive (12%, mean 349 nuclei per HPF; range, 284-440).…”

Section: Resultssupporting

confidence: 92%

“…The PBL also had a significant population of CD8-positive T cells, irrespective of the almost absent expression of MHCII/HLA by the neoplastic cells. 9 Importantly, together with CD8-positive T cells, there was a distinct population of PD1-positive T cells. In the PBL cases that we studied, EBV did not influence the immune populations, with regards to the content of TAM and CD8-positive and PD1-positive T cells quantified in the tissue.…”

Section: Discussionmentioning

confidence: 99%

“… 6 However EBV positivity in PBL has been found to be associated with increased expression of the programmed death ligand 1 (PD-L1) protein as well as other immune escape markers, 7 , 8 and decreased expression of major histocompatibility class II (MHCII)/human leukocyte A (HLA)-DR molecules by the neoplastic cells. 9 This has recently been found to be associated with increased antiviral cytotoxic immunity involving different immune cell populations. 7 …”

Section: Introductionmentioning

confidence: 99%

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Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma

et al. 2020

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Plasmablastic lymphoma mutational profile is undescribed. Here we performed a targeted exonic NGS analysis of 30 plasmablastic lymphoma cases with a B cell lymphoma dedicated panel and FISH for the detection of MYC rearrangements. A complete phenotyping of the neoplastic and microenvironment cell populations was also performed. We have identified an enrichment in recurrent genetic events in MYC (69% with MYC translocation or amplification and 3 cases with missense point mutations), PRDM1/Blimp1 and STAT3 mutations. These gene mutations were more frequent in EBV positive disease. Other genetic events included mutations in BRAF, EP300, BCR (CD79A and CD79B), NOTCH pathway (NOTCH2, NOTCH1 and SGK1) and MYD88pL265P. Immunohistochemical analysis showed consistent MYC expression, higher in cases with MYC rearrangements together with phospho-STAT3 (Tyr705) overexpression in cases with STAT3 SH2 domain mutations. Microenvironment populations were heterogeneous and unrelated with EBV, with an enrichment of Tumor Associated Macrophages (TAM) and PD1 positive T cells. PD-L1 was expressed in all cases in the TAM population but only in 5 cases in the neoplastic cells (4 out of 14 EBV positive cases). HLA expression was absent in the majority of PBL cases. In summary, Plasmablastic lymphoma mutational profile is heterogeneous and related with EBV infection. Genetic events in MYC, STAT3 and PRDM1/Blimp1 are more frequent in EBV positive disease. An enrichment in TAM and PD1 reactive T lymphocytes is found in the microenvironment of PBL cases, that express PD-L1 in the neoplastic cells in a fraction of cases.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma

et al. 2020

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“…Immunohistochemistry (IHC) [4, 30], photo microscopy [31], quantitative nuclease protection (qNPA) assays [32], CIITA expression by quantitative RT-PCR [33] and in vitro correlates [34] were all performed as previously described with additional details and modifications available in the supplemental methods, found on Leukemia Lymphoma Web site.…”

Section: Methodsmentioning

confidence: 99%

A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520

Puvvada

Liu

Rimsza

et al. 2016

Leukemia & Lymphoma

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Recent advances in diffuse large B-cell lymphomas (DLBCL) underscore the importance of tumor microenvironment in escaping host response. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5,13 months after registration for an overall response rate (ORR) of 10.5% (95 % CI 1.3-33.1%), and 3 patients had stable disease for 4.7, 42.3+, and 68.4+ months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining Vorinostat with R-CHOP.

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“…85,86 BLIMP1 represses genes that maintain the mature B-cell identity, such as PAX5, and promotes the expression of genes involved in plasma cell differentiation, such as XBP1. BLIMP1 also represses MYC and other genes controlling cell proliferation and cell growth.…”

Section: Dh/th Lymphomamentioning

confidence: 99%

Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification

Ott

Rosenwald

Campo

2013

Blood

223

214

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MYC is a potent oncogene initially identified as the target of the t(8;14)(q24;q32) chromosome translocation in Burkitt lymphoma. MYC gene alterations have been identified in other mature B-cell neoplasms that are usually associated with an aggressive clinical behavior. Most of these tumors originate in cells that do not normally express MYC protein. The oncogenic events leading to MYC up-regulation seem to overcome the inhibitory effect of physiological repressors such as BCL6 or BLIMP1.Aggressive lymphomas frequently carry additional oncogenic alterations that cooperate with MYC dysregulation, likely counteracting its proapoptotic function. The development of FISH probes and new reliable antibodies have facilitated the study of MYC gene alterations and protein expression in large series of patients, providing new clinical and biological perspectives regarding MYC dysregulation in aggressive lymphomas. MYC gene alterations in large B-cell lymphomas are frequently associated with BCL2 or BCL6 translocations conferring a very aggressive behavior. Conversely, MYC protein up-regulation may occur in tumors without apparent gene alterations, and its association with BCL2 overexpression also confers a poor prognosis. In this review, we integrate all of this new information and discuss perspectives, challenges, and open questions for the diagnosis and management of patients with MYC-driven aggressive B-cell lymphomas. (Blood. 2013;122(24):3884-3891) Introduction MYC was initially identified as the target oncogene dysregulated by the t(8;14)(q24;q32) translocation in Burkitt lymphoma (BL). MYC rearrangements involving the heavy-and light-chain immunoglobulin (IGL) loci and different non-IG genes were subsequently detected in other lymphoid neoplasms usually associated with very aggressive clinical behavior.1,2 The transforming oncogenic potential of MYC was initially demonstrated in cell lines and transgenic animal models. However, MYC dysregulation alone does not cause lymphoma, 4 and the t(8;14) has been found at very low levels in blood and BM of healthy individuals, 5 indicating that this genetic alteration per se is not sufficient to trigger lymphomagenesis. BL and most lymphomas carrying MYC translocations are among the most proliferative tumors. However, MYC expression has been difficult to identify in the germinal center (GC), the lymphoid cell compartment with the highest proliferative fraction, where most of these tumors originate. Understanding the possible role of MYC in normal lymphoid regulation and particularly the modulation of the GC reaction has been elusive.Recent studies, including basic immunology analyses, new animal models, next-generation sequencing, and clinicopathological observations, are converging to provide a new perspective of the role of MYC in the lymphoid system and the pathogenesis of aggressive lymphomas. In this review, we integrate all of this new information and discuss new perspectives, challenges, and open questions for the diagnosis and management of patients. MYC as a transc...

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Lack and/or aberrant localization of major histocompatibility class II (MHCII) protein in plasmablastic lymphoma

Cited by 13 publications

References 7 publications

Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma

Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma

A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520

Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification

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