PRDM1/Blimp1 downregulates expression of germinal center genes LMO2 and HGAL

Abstract

Human germinal center–associated lymphoma (HGAL) and LIM domain only-2 (LMO2) are proteins highly expressed in germinal center (GC) B lymphocytes. HGAL and LMO2 are also expressed in GC-derived lymphomas and distinguish biologically distinct subgroups of diffuse large B-cell lymphomas (DLBCL) associated with improved survival. However, little is known about their regulation. PRDM1/Blimp-1 is a master regulator of terminal B cell differentiation and may also function as a tumor suppressor in the pathogenesis of DLBCL, where it is frequently inactivated by mutations and deletions. We now demonstrate that both HGAL and LMO2 are directly regulated by the transcription repressor PRDM1. In vivo studies demonstrate that PRDM1 directly binds to the recognition sites within the upstream promoters of both HGAL and LMO2. PRDM1 binding suppresses endogenous protein and mRNA levels of HGAL and LMO2. In addition promoter analysis reveals that site specific binding of PRDM1 to the promoters is capable of repressing transcriptional activity. This inhibitory effect of PRDM1 suggests that it has a key role in the loss of HGAL and LMO2 expression upon differentiation of GC B cells to plasma cells and may also contribute to absence of HGAL and LMO2 expression in post-GC lymphoid tumors.

Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

“…Our lab and others have previously demonstrated that PRDM1 directly suppresses components of activated B cells, suggesting that PRDM1 might have a key role in regulating ELL family expression (47, 52, 53). In Figures 1A, 2B and Figure 1C, the expression of PRDM1 is shown to coincide with loss of ELL3 expression.…”

miR-155 regulates HGAL expression and increases lymphoma cell motility

“…8 B-cell receptor 29,30 and/or NFB activation 32 during GC lymphocyte differentiation process can up-regulate miR-155 and PRDM1 expression leading to decreased HGAL protein expression, increasing lymphocyte motility and potentially affecting egress from GC. As shown herein and in our previous work, both miR-155 and PRDM1 directly regulate HGAL expression, 8 and overexpression of PRDM1 in DLBCL cell lines is not increasing miR-155 expression (data not shown). Overall, our current observations extend our previous findings on HGAL regulation by the PRDM1 8 and identify a novel role of miR-155 in immune system.…”

“…As shown herein and in our previous work, both miR-155 and PRDM1 directly regulate HGAL expression, 8 and overexpression of PRDM1 in DLBCL cell lines is not increasing miR-155 expression (data not shown). Overall, our current observations extend our previous findings on HGAL regulation by the PRDM1 8 and identify a novel role of miR-155 in immune system. miR-155 is also implicated in pathogenesis of lymphoid malignancies.…”

“…We showed that PRDM1 directly binds to the recognition sites within the upstream promoter of HGAL and transcriptionally suppresses its endogenous mRNA and protein levels. 8 However, additional factors most probably contribute to the restricted and tightly regulated expression of HGAL in GC lymphocytes and GC-derived lymphomas.…”

“…We showed that PRDM1 directly binds to the recognition sites within the upstream promoter of HGAL and transcriptionally suppresses its endogenous mRNA and protein levels. 8 However, additional factors most probably contribute to the restricted and tightly regulated expression of HGAL in GC lymphocytes and GC-derived lymphomas.microRNAs (miRNAs) are small noncoding RNAs that posttranscriptionally regulate expression of genes controlling multiple biologic processes. 9 The stage-specific expression of certain miRNAs in the immune system 10 suggests their participation in immune system regulation that may contribute to pathogenesis of lymphocyte-derived malignancies.…”