BLIMP1α, the master regulator of plasma cell differentiation is a tumor supressor gene in B cell lymphomas

Vrzalikova, Katerina; Woodman, Ciaran; Murray, Paul G.

doi:10.5507/bp.2012.003

Cited by 17 publications

(21 citation statements)

References 75 publications

(95 reference statements)

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“…64 It is believed that this short form acts as a dominant negative inhibitor. 41,63 In agreement with previous findings showing that PRDM1b retains only 50% of the ability to repress MYC, 41 we demonstrate that PRDM1b has a reduced antiproliferative effect in cHL cell lines. We propose that PRDM1b expression provides an advantage for HRS cells by interfering with the function of residual PRDM1a.…”

supporting

confidence: 81%

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma

Vogel

Xie

Guan

et al. 2014

Blood

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Key Points• FOXO1 directly activates PRDM1a, the master regulator of PC differentiation, and it enriches a PC signature in cHL cell lines. • PRDM1a is a tumor suppressor in cHL.The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-kB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation.Here we show that FOXO1 directly upregulates the full-length isoform PRDM1a in cHL cell lines. We also observed a positive correlation between FOXO1 and PRDM1 expression levels in primary Hodgkin-Reed-Sternberg cells. Further, we show that PRDM1a acts as a tumor suppressor in cHL at least partially by blocking MYC. Here we provide a link between FOXO1 repression and PRDM1a downregulation in cHL and identify PRDM1a as a tumor suppressor in cHL. The data support a potential role for FOXO transcription factors in normal PC differentiation. (Blood. 2014;124(20):3118-3129) IntroductionClassical Hodgkin lymphoma (cHL) differs from other B-cell lymphomas by a unique phenotype of the malignant cells of cHL, Hodgkin and Reed-Sternberg (HRS) cells, characterized by loss of the B-cell program and by the formation of a reactive infiltrate harboring these cells. 1 The repression of the B-cell program in HRS cells is characterized by downregulation of critical B-cell transcription factors, 2 including BCL6. 3 The oncogenic program of cHL is based on the constitutive activation of JAK/STAT, NF-kB, ERK, and PI3K/AKT pathways. [4][5][6][7] Ultimate targets of these pathways are the protooncogenic transcription factors MYC and IRF4. 8,9 Of note, NF-kB, STAT3, and IRF4 converge to induce plasma cell (PC) differentiation in normal B cells by upregulation of the PC master transcription factor PRDM1/BLIMP-1. [10][11][12] Surprisingly, HRS cells express only low levels of PRDM1 and other PC markers. 3,13 PRDM1 acts as a tumor suppressor in diffuse large B-cell lymphoma of the activated B-cell type (ABC-DLBCL), whose oncogenic program resembles that of cHL, including dependency on constitutive NF-kB and JAK-STAT activation and high expression of IRF4. 1,8,14,15 Of note, NF-kB activation in B cells results in the development of lymphomas only when Prdm1 is deleted. 16 We found that FOXO1, which is highly expressed in B cells and in different types of non-Hodgkin lymphoma, is downregulated in cHL. Overexpression of a constitutively active FOXO1 protein induces growth arrest and apoptosis in cHL cell lines.17 FOXO1 belongs to the forkhead box (Fhbox) family of transcription factors that regulates different physiological processes including cell death, differentiation, and oxidative stress.18 FOXO1 plays a central role in the early stages of B-cell differentiation, 19 and it is essential for the expression of B-cell-specific genes such as BCL6, AICDA, an...

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supporting

confidence: 81%

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma

Vogel

Xie

Guan

et al. 2014

Blood

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“…Transcriptional activation is uncharacteristic of BLIMP1, given that it usually functions as a repressor (46,48,50,53,81,82). Thus, for a control, we examined likewise the effect of BLIMP1 addition on transcription from the promoter of the cellular gene CIITA.…”

Section: Versus Lane 5)mentioning

confidence: 99%

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

Reusch

Nawandar

Wright

et al. 2015

J Virol

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Epstein-Barr virus (EBV) maintains a lifelong latent infection within a subset of its host IMPORTANCEThis study is the first one to show that the cellular transcription factor BLIMP1, a key player in both epithelial and B-cell differentiation, induces reactivation of the oncogenic herpesvirus Epstein-Barr virus (EBV) out of latency into lytic replication in a variety of cancerous epithelial cell types as well as in some, but not all, B-cell types that contain this virus in a dormant state. The mechanism by which BLIMP1 does so involves strongly turning on expression of both of the immediate early genes of the virus, probably by directly acting upon the promoters as part of protein complexes or indirectly by altering the expression or activities of some cellular transcription factors and signaling pathways. The fact that EBV ؉ cancers usually contain mostly undifferentiated cells may be due in part to these cells dying from lytic EBV infection when they differentiate and express wild-type BLIMP1.

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“…The physiological signals that drive normal B-cell differentiation towards plasma cells are absent in EBV-transformed cells [35][36][37]. BLIMP1α is a tumor suppressor transcription factor that is required for plasma cell differentiation and is inactivated in a subset of diffuse large B-cell lymphoma -ABC subtype [35][36][37]. BLIMP1α is encoded by PRDM1 gene and represes genetic programms associated with GC stages of B-cells, promotes cell cycle exit and prime plasma cells for apoptosis due to down-regulation of anti-apoptotic genes [35][36][37].…”

Section: The Historymentioning

confidence: 99%

“…The suppresion of viral replication is an important pathogenetic event in Epstein-Barr virus associated lymphomas [35][36][37]. The physiological signals that drive normal B-cell differentiation towards plasma cells are absent in EBV-transformed cells [35][36][37]. BLIMP1α is a tumor suppressor transcription factor that is required for plasma cell differentiation and is inactivated in a subset of diffuse large B-cell lymphoma -ABC subtype [35][36][37].…”

Section: The Historymentioning

confidence: 99%

“…The EBV is usually detected by in situ hybridization -EBER ISH -and most cases are aslo LMP1 or LMP2 positive by immunohistochemistry [1,25]. The suppresion of viral replication is an important pathogenetic event in Epstein-Barr virus associated lymphomas [35][36][37]. The physiological signals that drive normal B-cell differentiation towards plasma cells are absent in EBV-transformed cells [35][36][37].…”

Section: The Historymentioning

confidence: 99%

See 1 more Smart Citation

Diffuse large B-cell lymphoma: The history, current view and new perspectives

Flodr¹,

Latálová²,

Tichý³

et al. 2014

neo

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The basic principles of lymphoma classification(s) in general have been widely evolving in a course of decades of years wiht the use of contemporary resources and recent cutting edges in hematooncology on a clinical, morphological and molecular level bring new possibilities not only in improvements of diagnostic and prognostic algorithms and also bear new opportunities in so called targeted and tailored strategies of lymphoma therapy. The pathogenesis and biologic behavior of lymphoproliferations and even lymphomas should be studied in a context of lymphocytic and (neoplastic) lymphoid stage and chronologic development. In a current more complex insight into lymphoproliferations we would like to describe huge heterogeneity of diffuse large B-cell lymphoma in relationship to mandatory WHO classification since 2008 and the next development of knowledge in this field with potential new influence on an advancement of both classification and therapy.

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BLIMP1α, the master regulator of plasma cell differentiation is a tumor supressor gene in B cell lymphomas

Cited by 17 publications

References 75 publications

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

Diffuse large B-cell lymphoma: The history, current view and new perspectives

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