SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity

Abstract

Interferon regulatory factor 4 (IRF4) is central to the transcriptional network of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive lymphoma subgroup defined by gene expression profiling. Since cofactor association modifies transcriptional regulatory input by IRF4, we assessed genome occupancy by IRF4 and endogenous cofactors in ABC-DLBCL cell lines. IRF4 partners with SPIB, PU.1 and BATF genome-wide, but SPIB provides the dominant IRF4 partner in this context. Upon SPIB knockdown IRF4 occupancy is depleted and neither PU.1 nor BATF acutely compensates. Integration with ENCODE data from lymphoblastoid cell line GM12878, demonstrates that IRF4 adopts either SPIB- or BATF-centric genome-wide distributions in related states of post-germinal centre B-cell transformation. In primary DLBCL high-SPIB and low-BATF or the reciprocal low-SPIB and high-BATF mRNA expression links to differential gene expression profiles across nine data sets, identifying distinct associations with SPIB occupancy, signatures of B-cell differentiation stage and potential pathogenetic mechanisms. In a population-based patient cohort, SPIBhigh/BATFlow-ABC-DLBCL is enriched for mutation of MYD88, and SPIBhigh/BATFlow-ABC-DLBCL with MYD88-L265P mutation identifies a small subgroup of patients among this otherwise aggressive disease subgroup with distinct favourable outcome. We conclude that differential expression of IRF4 cofactors SPIB and BATF identifies biologically and clinically significant heterogeneity among ABC-DLBCL.

B-Cell Receptor Signaling in Diffuse Large B-Cell lymphoma

“…Thus, disrupting IRF4 activity is toxic to ABC DLBCLs due to the collapse of both pro-survival NF-κB signaling and suicide by autocrine induction of interferon [15]. Finally, IRF4 has been found to have an additional binding partner in lymphocytes, BATF, which can influence the spectrum of genes targeted during activation and differentiation [17, 18]. IRF4 and BATF are required downstream of BCR signaling to promote transcriptional programs during GC formation [17].…”

“…IRF4 and BATF are required downstream of BCR signaling to promote transcriptional programs during GC formation [17]. The association of IRF4 with SPIB versus BATF generates heterodimeric transcription factors that control distinct and developmentally-related gene expression programs in DLBCL, and they can been used to identify a subset of ABC DLBCL patients (SPIB-high/BATF-low) with MYD88 L265P who may have a better clinical outcome [18]. Thus, oncogenic signaling downstream of the BCR creates multiple self-reinforcing survival signals through the amplification of various NF-κB transcriptional networks in ABC DLBCL.…”

A gene expression signature‐based nomogram model in prediction of breast cancer bone metastases

“…It has been found that REEP1 could facilitate mitochondrial‐ER interactions, which may result in intracellular Ca 2+ overload and axonal damage, and REEP1 variants were recognized as causes of Neurological Disease like hereditary spastic paraplegia (HSP) and distal hereditary motor neuropathy (dHMN) . The third gene SPIB, encoding an ETS‐domain transcription factor, was believed to be associated with cancers especially in lymphomas . Also, Yi‐Jung et al found the SPIB may be involved in tumorigenesis in live cancer, and Wei et al reported that SPIB is expressed in invasive cancer cells in human primary lung cancer tissues.…”

“…37 The third gene SPIB, encoding an ETS-domain transcription factor, was believed to be associated with cancers especially in lymphomas. 38,39 Also, Yi-Jung et al 40 found the SPIB may be involved in tumorigenesis in live cancer, and Wei et al 41 reported that SPIB is expressed in invasive cancer cells in human primary lung cancer tissues. ALDH3B2 was widely known as a member of aldehyde dehydrogenases (ALDHs).…”

OSdlbcl: An online consensus survival analysis web server based on gene expression profiles of diffuse large B‐cell lymphoma

“…To establish OSdlbcl web server, we downloaded one TCGA cohort and six GEO cohorts with gene expression profiles and clinical follow-up information ( Table 1). [15][16][17][18][19][20][21][22][23] A total of 1100 unique DLBCL cases were collected, all of which have available gene expression profiling data and clinical followup survival information. Overall survival (OS) is the most important endpoint for the clinical outcomes in OSdlbcl.…”