The significance of FOXP1 in diffuse large B-cell lymphoma

Gascoyne, Duncan M.; Banham, Alison H.

doi:10.1080/10428194.2016.1228932

Cited by 51 publications

(43 citation statements)

References 99 publications

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“…The prognostic value of multiple other gene mutations such as TP53 , MYD88 , FOXP1 , and FOXP2 in DLBCL has been suggested previously [22, 23, 40, 41]. In our cohort, TP53 -mutated cases had worse OS, but this difference did not reach statistical significance.…”

Section: Discussioncontrasting

confidence: 40%

Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort

et al. 2017

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Background/purposeRecently, the mutational background of diffuse large B cell lymphoma (DLBCL) has been revealed, identifying specific genetic events that drive lymphomagenesis. However, the prognostic value of these mutations remains to be determined. Prognostic biomarkers in DLBCL are urgently needed, since the current clinical parameter-based factors (e.g., International Prognostic Index (IPI)) are insufficient, particularly in identifying patients with poor prognosis who might benefit from alternative treatments.MethodsWe investigated the prognostic value of somatic mutations in DLBCL in a clinical trial (NCT00544219) patient cohort homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary endpoint was event-free survival (EFS) at 2 years. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Targeted high-throughput sequencing (HTS) of tumor genomic DNA was performed on all exons or hotspots of 68 genes frequently mutated in B cell lymphomas. Mutational data was correlated with the endpoints to identify prognostic associations.ResultsTargeted HTS detected somatic mutations in 71/76 (93%) of investigated cases. The most frequently mutated genes were KMT2D, SOCS1, GNA13, and B2M. Survival analysis revealed that CREBBP- and EP300-mutated cases had significantly worse OS, PFS, and EFS. In addition, ATM mutations predicted worse outcomes for all three clinical endpoints in germinal center B cell-like DLBCL. In contrast, SOCS1 mutations were associated with better PFS. On multivariable analysis taken into account IPI and failure to achieve complete remission, CREBBP and EP300 mutations remained significant to predict worse OS, PFS, and EFS.ConclusionTargeted mutation analysis of a uniformly treated prospective clinical trial DLBCL cohort identifies tumor-based genetic prognostic markers that could be useful in the clinical management of such patients.Trial registrationClinicalTrials.gov NCT00544219Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0438-7) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 40%

Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort

et al. 2017

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“…On the other hand, S1PR2 was expressed more strongly in follicle centers than in mantle zones (Figure 1), which consistent with the S1PR2 mRNA expression studies described previously in mice 23 and sorted human tonsillar B cells 24 ; in addition, S1PR2-staining was specific for S1PR2 when tested with control cell lines (Figure 1). FOXP1 staining was consistent with described patterns 20 such that FOXP1 was more strongly expressed in mantle zones than follicle centers (Figure 1). Lastly, phospho-STAT3 showed scattered staining in reactive follicles and interfollicular areas, including vascular endothelial cells and scattered stromal cells (Figure 1), consistent with reported staining patterns 5, 16 .…”

Section: Resultssupporting

confidence: 83%

“…FOXP1 (Forkhead box protein P1) is a transcription factor that is expressed in a subset of GCB-DLBCL, and to a greater extent in ABC-like DLBCL, and may be associated with a poorer overall survival according to some studies 13, 20 . According to some studies, FOXP1 expression correlates with MYC expression 20 and in a limited series of 11 cases of Triple Hit Lymphoma (ie, B Cell Lymphomas with MYC, BCL2 and BCL6 translocations), all 11 cases were positive for FOXP1 21 . However, FOXP1 expression in BL and HGBL-DH has yet to be adequately explored.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of S1PR1/pSTAT3 and S1PR2/FOXP1 Expression in Aggressive, Mature B Cell Lymphomas

Al-Kawaaz

Sánchez

Kluk

2018

Preprint

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Aggressive, mature B-cell lymphomas represent a heterogeneous group of diseases including Burkitt Lymphoma (BL), High Grade B Cell Lymphomas (HGBL) (eg, Double-Hit B cell lymphomas (HGBL-DH: HGBL with MYC and BCL2 and/or BCL6 translocations)), HGBL, Not Otherwise Specified (HGBL, NOS) and Diffuse Large B Cell Lymphoma.The overlapping morphologic and immunohistochemical features of these lymphomas may pose diagnostic challenges in some cases, and a better understanding of potential diagnostic biomarkers and possible therapeutic targets is needed. Sphingosine 1 Phosphate Receptors (S1PR1-5) represent a family of G-protein coupled receptors that bind the sphingolipid (S1P) and influence migration and survival pathways in a variety of cell types, including lymphocytes. S1PRs are emerging as biomarkers in B cell biology and interaction between S1PR pathways and STAT3 or FOXP1 has been reported, especially in DLBCL.Our aim was to extend the understanding of the S1PR1, STAT3 and S1PR2, FOXP1 expression beyond DLBCL, into additional aggressive, mature B cell lymphomas such as BL, HGBL-DH and HGBL,NOS.Herein, we report that S1PR1 and S1PR2 showed different patterns of expression in mantle zones and follicle centers in reactive lymphoid tissue and, among the lymphomas in this study, Burkitt lymphomas showed a unique pattern of expression compared to HGBL and DLBCL. Additionally, we found that S1PR1 and S1PR2 expression was typically mutually exclusive and were expressed in a low proportion of cases (predominantly HGBL involving extranodal sites). Lastly, FOXP1 was expressed in a high proportion of the various case types and pSTAT3 was detected in a significant proportion of HGBL and DLBCL cases. Taken together, these findings provide further evidence that S1PR1, pSTAT3, S1PR2 and FOXP1 play a role in a subset of aggressive mature B cell lymphomas.STAT3 is a transcription factor which regulates tumorigenesis in a variety of lymphoproliferative disorders and is therapeutically targetable 11, 12 . pSTAT3 has been reported to be a potential biomarker in DLBCL which may depend on anatomic location, according to one study 13 . STAT3 was reported to show high levels of expression and phosphorylation in ABC-DLBCL 14 . Interestingly, STAT3 was found to be a direct transcriptional activator of S1PR1 expression in various cell types 15 . In DLBCL, S1PR1 over-expression has been reported in approximately 6-40% of DLBCL and was associated with STAT3 phosphorylation in fresh tissue and as well as a negative prognosis 5, 16 . Additional studies, using primary tumor cells, have also shown phospho-STAT3 activity correlated with increased S1PR1 expression in ABC-DLBCL 17 , and that S1PR1 could activate STAT3 in ABC-DLBCL 17 .Furthermore, inhibition of S1PR1 expression, down-regulated STAT3 activity and caused growth inhibition of lymphoma cells 17 . In BL, phosphorylated STAT3 was reported to be associated with multidrug resistance according to one study 18 , however, the expression of phosphorylated STAT3does not appear to have been adequ...

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“…High FOXP1 expression can contribute to B-cell lymphomagenesis by promoting B-cell survival inhibiting plasma cell differentiation. The small FOXP1 isoform (FOXP1-iso) is predominantly expressed in ABC-DLBCL, and studying its oncogenic potential and transcriptional activity is directly compared to FOXP1-FL in DLBCL cell lines and primary human B cells [61][62][63][64].…”

Section: Activated B-cell-like (Abc)mentioning

confidence: 99%

B Cell Lymphomagenesis

Škunca¹

2020

Normal and Malignant B-Cell

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Lymphoid neoplasms are a heterogeneous group of malignancies whose diagnosis depends on a very good analysis of hematopathology and morphology, immunophenotype, cytogenetic, molecular, and clinical characteristics. B-cell lymphomas begin from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. The evolution of B-cell lymphomagenesis depends on different numbers of signal pathways. Proteins that play key point of signaling networks are changed by aberrant chromosomal expression, translocation, and/or accumulation, and those events determine the fate of the affected B cells. Many chemokines and cytokines have been implicated in providing the line for the cellular surviving and interaction in lymphoid organogenesis. Specific chromosomal alterations were associated with significant changes in gene-expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma. The goal of this study was to find out a correlation between tumor markers and survival in patients with subgroups of DLBCL. The goal is to find out chronic autoimmune or pathogen-induced immune reactions resulting in lymphoid neogenesis. So we address (i) chemokines and adhesion molecules involved in lymphoid neogenesis, (ii) the autoimmune diseases and pathogens which are associated with the development of B-cell lymphomas, and (iii) the molecular mechanisms involved in the initiation and progression of DLBCL.

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The significance of FOXP1 in diffuse large B-cell lymphoma

Cited by 51 publications

References 99 publications

Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort

Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort

Evaluation of S1PR1/pSTAT3 and S1PR2/FOXP1 Expression in Aggressive, Mature B Cell Lymphomas

B Cell Lymphomagenesis

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