Activating mutations in CD79 and MYD88 have recently been found in a subset of diffuse large B-cell lymphoma (DLBCL), identifying B-cell receptor and MYD88 signalling as potential therapeutic targets for personalized treatment. Here, we report the prevalence of CD79B and MYD88 mutations and their relation to established clinical, phenotypic and molecular parameters in a large panel of DLBCLs. We show that these mutations often coexist and demonstrate that their presence is almost mutually exclusive with translocations of BCL2, BCL6 and cMYC, or Epstein–Bar virus infection. Intriguingly, MYD88 mutations were by far most prevalent in immune-privileged site-associated DLBCL (IP-DLBCL), presenting in central nervous system (75%) or testis (71%) and relatively uncommon in nodal (17%) and gastrointestinal tract lymphomas (11%). Our results suggest that MYD88 and CD79B mutations are important drivers of IP-DLBCLs and endow lymphoma-initiating cells with tissue-specific homing properties or a growth advantage in these barrier-protected tissues.
REFERENCES1 Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009; 114: 2984-2992. 2 Cortes JE, Perl AE, Dombret H, Kayser S, Steffen B, Rousselot P et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of Quizartinib (AC220) in patientsZ60 years of age with FLT3 ITD positive or negative relapsed/refractory. AML Blood (ASH Ann Meeting Abstr) 2012; 120: Abstract 48. 3 Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.
Key Points• FOXP1 directly represses multiple proapoptotic genes in primary mature human B cells and DLBCL cell lines.• FOXP1 cooperates with NF-kB signaling to promote expansion of primary mature human B cells by inhibition of caspase-dependent apoptosis.The forkhead transcription factor FOXP1 is involved in B-cell development and function and is generally regarded as an oncogene in activated B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue lymphoma, lymphomas relying on constitutive nuclear factor kB (NF-kB) activity for survival. However, the mechanism underlying its putative oncogenic activity has not been established. By gene expression microarray, upon overexpression or silencing of FOXP1 in primary human B cells and DLBCL cell lines, combined with chromatin immunoprecipitation followed by next-generation sequencing, we established that FOXP1 directly represses a set of 7 proapoptotic genes. Low expression of these genes, encoding the BH3-only proteins BIK and Harakiri, the p53-regulatory proteins TP63, RASSF6, and TP53INP1, and AIM2 and EAF2, is associated with poor survival in DLBCL patients. In line with these findings, we demonstrated that FOXP1 promotes the expansion of primary mature human B cells by inhibiting caspase-dependent apoptosis, without affecting B-cell proliferation. Furthermore, FOXP1 is dependent upon, and cooperates with, NF-kB signaling to promote B-cell expansion and survival. Taken together, our data indicate that, through direct repression of proapoptotic genes, (aberrant) expression of FOXP1 complements (constitutive) NF-kB activity to promote B-cell survival and can thereby contribute to B-cell homeostasis and lymphomagenesis. (Blood. 2014;124(23):3431-3440) IntroductionThe forkhead transcription factor FOXP1 plays an important role in a wide diversity of biological processes, including T-cell development and differentiation 1,2 and B-cell development and function. [3][4][5] Furthermore, FOXP1 has long been recognized as a potential oncogene in various types of B-cell non-Hodgkin lymphomas; however, its mode of oncogenic action is largely unknown. 6,7 In diffuse large B-cell lymphoma (DLBCL) and mucosaassociated lymphoid tissue (MALT) lymphoma, aberrantly high expression of FOXP1 is associated with poor prognosis and FOXP1-positive MALT lymphomas were shown to be at risk of transforming into aggressive DLBCLs. 8,9 This overexpression of FOXP1 can be caused by a t(3;14)(p14;q32) translocation, involving FOXP1 and IgH loci, which has recurrently been observed in MALT lymphoma and activated B-cell-like (ABC) DLBCL.10-13 FOXP1 expression is also frequently upregulated in ABC-DLBCL as a result of trisomy 3 or more restricted focal amplifications, 14 whereas aberrant Myc expression in transformed gastric MALT lymphomas leads to upregulation of FOXP1 due to repression of the FOXP1 targeting miRNA 34a. 15 Furthermore, expression levels of FOXP1 can be used as a discriminator between the ABC and germinal center (GC) subtypes of DLBCL, ...
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