Plasmablastic lymphoma phenotype is determined by genetic alterations in MYC and PRDM1

Montes‐Moreno, Santiago; Martinez, Nerea; Zecchini-Barrese, Tomás; Villambrosía, Sonia González de; Linares, Emma; Ranchal, Tamara; Rodríguez-Pinilla, María; Batlle, Ana; Cereceda-Company, Laura; Revert-Arce, Jose Bernardo; Almaráz, Carmen; Piris, Miguel Á.

doi:10.1038/modpathol.2016.162

Cited by 66 publications

(104 citation statements)

References 39 publications

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“…Surprisingly, BLIMP1 genetic aberrations are also found in a fraction of PBL and MM (Chapman et al, 2011; Montes-Moreno et al, 2017). Their impact on BLIMP1 activity, timing of occurrence, disease formation and/or progression requires investigation.…”

Section: Discussionmentioning

confidence: 99%

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

Barbosa

D’Andrea

et al. 2020

Preprint

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Highlights 28 • NF-kB and MYC co-activation originates (pre)plasmablast-like cancer 29 • NF-kB/MYC + renders cancer cells addicted to IL6 for survival and phenotypic stability 30 • NF-kB/MYC + cancers are alike a fraction of human plasmablastic lymphoma 31 • t(8;14)[MYC-IGH] multiple myeloma is linked to a NF-kB/MYC co-activation signature 32 33 2 Summary 34 NF-kB and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-kB is 35 necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus 36 unclear if NF-kB/MYC co-deregulation is developmentally compatible in carcinogenesis and/or impacts 37 cancer cell differentiation state, possibly uncovering unique sensitivities. Using a mouse system to trace 38 cell lineage and oncogene activation we found that NF-kB/MYC co-deregulation originated cancers with a 39 plasmablast-like phenotype, alike human plasmablastic-lymphoma and was linked to t(8;14)[MYC-40 IGH] multiple myeloma. Notably, in contrast to NF-kB or MYC activation alone, co-deregulation rendered 41 cells addicted to IL6 for survival and phenotypic stability. We propose that conflicting oncogene-driven 42 differentiation pressures can be accommodated at a cost in poorly-differentiated cancers. 43 44 Significance 45 Our studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of 46 NF-kB and MYC synergize in forming a cancer with a poorly-differentiated state. The cancers in the mouse 47 system share features with human Plasmablastic lymphoma that has a dismal prognosis and no standard of 48 care, and with t(8;14)[MYC-IGH] Multiple myeloma, which is in overall resistant to standard therapy. 49 Notably, we found that NF-kB and MYC co-deregulation uniquely render cells sensitive to IL6 deprivation, 50 providing a road-map for patient selection. Because of the similarity of the cancers arising in the compound 51 mutant mouse model with that of human Plasmablastic lymphoma and t(8;14)[MYC-IGH] Multiple 52 myeloma, this model could serve in preclinical testing to investigate novel therapies for these hard-to-treat 53 diseases. 54 55 Keywords 56 NF-kB, MYC, IL6, B-cell, plasma-cell, plasmablast, B-cell terminal differentiation, Diffuse large B-cell 57 lymphoma, plasmablastic lymphoma, multiple myeloma, phenotypic stability 58 59 60 61 62 63 64 65 66 67 90 Tornatore et al., 2014). 91 92 The knowledge that NF-kB directly induces the expression of genes essential in B-to-plasma cell 93 differentiation and that ABC-DLBCL cancer cells despite being mature B-cells display features of 94 plasmacytic differentiation suggest that a block of B-to-plasma cell is required in the pathogenesis of ABC-95 DLBCL. Consistently, the activity of BLIMP1, key for B-to-plasma cell differentiation, is lost exclusively 96 in DLBCL of the ABC subtype through BLIMP1 genetic aberrations (∼30% of cases), and indirectly by 97 deregulated BCL6 expression from chromosomal translocations (∼26% of cases) (Mandelbaum et al.,98 2010; Pasqualuc...

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Section: Discussionmentioning

confidence: 99%

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

Barbosa

D’Andrea

et al. 2020

Preprint

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“…PRDM1 mutations contribute to the oncogenicity of MYC in PBL. Aberrant coexpression of MYC and PRDM1 / Blimp1a due to genetic changes is responsible for the phenotype of PBL . Dysregulation of MYC may also impart plasmablastic morphology and an aggressive clinical course to B‐cell neoplasms ata later stage of differentiation .…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant coexpression of MYC and PRDM1/Blimp1adue to genetic changes is responsible for the phenotype of PBL. 29 Dysregulation of MYC may also impart plasmablastic morphology and an aggressive clinical course to B-cell neoplasms ata later stage of differentiation. 18 The important role of MYC in PBL suggests that its targeted inactivation may be a rational and effective therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

High incidence of MYC rearrangement in human immunodeficiency virus‐positive plasmablastic lymphoma

et al. 2019

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Aims MYC rearrangements are the main cytogenetic alterations in plasmablastic lymphoma (PBL). We aimed to investigate the relationship between MYC rearrangement and the clinicopathological features of PBL. Methods and results MYC rearrangements assessed in 13 unpublished single‐centre PBL cases, and an additional 85 cases from the literature, with reported MYC rearrangement information individualised by patient, were reviewed. In Asia, PBL was much less commonly diagnosed in human immunodeficiency virus (HIV)‐positive patients (27% versus 84%, P = 0.000), with older age (median age at diagnosis: 52 years versus 44 years, P = 0.046) and a lower EBV infection rate (56.8% versus 81.8%, P = 0.049), than in non‐Asian regions. Overall, MYC rearrangements were identified in 44 of 98 (44.9%) PBL cases, and IGH was the partner in almost all available cases (30/31, 96.8%), as confirmed with a MYC–IGH fusion probe. The MYC rearrangement rate in HIV‐positive cases (33/55, 60.0%) was significantly higher than that in HIV‐negative cases (11/38, 28.9%, P = 0.003). Patients with MYC rearrangement showed a trend towards an inferior median survival time (9.6 months versus 15.7 months, P = 0.122) and 2‐year overall survival (17% versus 32%, P = 0.238). Conclusions MYC rearrangement was frequently identified in PBL patients, and IGH was the partner gene in an overwhelming majority of MYC rearrangements. In addition, the MYC rearrangement rate was significantly higher in HIV‐positive PBL patients than that in HIV‐negative patients. MYC rearrangement may play an important role in the pathogenesis of HIV‐positive PBL, but further studies are required to understand the underlying mechanisms.

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“…As mentioned earlier, both PPCM and PBL are associated with MYC aberrations. In fact, these gene aberrations have been shown to be present in 30–70% of all PBL cases, leading some to claim that a MYC aberration could be useful for PBL diagnosis. However, MYC aberrations are not useful for differentiating PBL from PPCM, and, in fact, are thought to contribute to the plasmablastic morphology of both of these entities .…”

Section: Discussionmentioning

confidence: 99%

CD117 (KIT) is a useful marker in the diagnosis of plasmablastic plasma cell myeloma

2017

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Plasmablastic lymphoma phenotype is determined by genetic alterations in MYC and PRDM1

Cited by 66 publications

References 39 publications

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

High incidence of MYC rearrangement in human immunodeficiency virus‐positive plasmablastic lymphoma

CD117 (KIT) is a useful marker in the diagnosis of plasmablastic plasma cell myeloma

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