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The hematopoietic oncoprotein FOXP1 promotes cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling


Flori, Michael. The hematopoietic oncoprotein FOXP1 promotes cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling. 2016, University of Zurich, Faculty of Science.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non- Hodgkin lymphoma. With current treatment regimens, a substantial part of DLBCL patients can be cured. However, up to 40% will not achieve durable remissions and eventually will succumb to recurrent disease. Using gene expression profiling, two major subtypes called ABC (activated B-cell like) and GCB (germinal center B-cell like) DLBCL have been identified. This is of significant prognostic value, since ABC-DLBCL patients fare worse with a 5- year survival rate of 35% compared to 60% of GCB-DLBCL patients.
One hallmark of ABC-DLBCL is aberrant high expression of the oncogenic transcription factor forkhead box protein 1 (FOXP1), which also plays a crucial role during normal B-cell development. Over-expression of FOXP1 is a very strong predictor of poor prognosis and can result from isolated gains of 3p14.1, trisomy 3 and translocations juxtaposing FOXP1 to Immunoglobulin (Ig) and non-Ig genes. We have shown an alternative mechanism of FOXP1 dysregulation due to lack of post-transcriptional regulation by the microRNA miR-34a, which targets FOXP1. In DLBCL cell lines, forced expression of miR-34a or knock-down of FOXP1 inhibited cell growth and induced apoptosis.
Herein, I aimed to elucidate the target genes of miR-34a in DLBCL cell lines, particularly genes involved in the induction of apoptosis. I further strived to identify target genes of FOXP1 in DLBCL, in order to elucidate possibly druggable signaling pathways downstream of FOXP1 and shed further light on the oncogenesis of DLBCL.
In this work, I was able to show that FOXP1 represses the transcription of the sphingosine 1-phosphate receptor 2 (S1PR2) gene. Moreover, expression of FOXP1 and S1PR2 negatively correlate in DLBCL patients and expression of S1PR2 harbors prognostic information for DLBCL patients. Over-expression of S1PR2 led to the induction of apoptosis in DLBCL cell lines and inhibited tumor growth in vitro and in vivo. I was further able to show that the induction of apoptosis by over-expressing S1PR2 was mediated by the downstream G-protein Gα13. S1PR2 and GNA13 are co- expressed in normal B-cell subsets and were previously demonstrated as frequently mutated in GCB-DLBCL patients, confirming their pivotal roles as tumor suppressor genes in DLBCL.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non- Hodgkin lymphoma. With current treatment regimens, a substantial part of DLBCL patients can be cured. However, up to 40% will not achieve durable remissions and eventually will succumb to recurrent disease. Using gene expression profiling, two major subtypes called ABC (activated B-cell like) and GCB (germinal center B-cell like) DLBCL have been identified. This is of significant prognostic value, since ABC-DLBCL patients fare worse with a 5- year survival rate of 35% compared to 60% of GCB-DLBCL patients.
One hallmark of ABC-DLBCL is aberrant high expression of the oncogenic transcription factor forkhead box protein 1 (FOXP1), which also plays a crucial role during normal B-cell development. Over-expression of FOXP1 is a very strong predictor of poor prognosis and can result from isolated gains of 3p14.1, trisomy 3 and translocations juxtaposing FOXP1 to Immunoglobulin (Ig) and non-Ig genes. We have shown an alternative mechanism of FOXP1 dysregulation due to lack of post-transcriptional regulation by the microRNA miR-34a, which targets FOXP1. In DLBCL cell lines, forced expression of miR-34a or knock-down of FOXP1 inhibited cell growth and induced apoptosis.
Herein, I aimed to elucidate the target genes of miR-34a in DLBCL cell lines, particularly genes involved in the induction of apoptosis. I further strived to identify target genes of FOXP1 in DLBCL, in order to elucidate possibly druggable signaling pathways downstream of FOXP1 and shed further light on the oncogenesis of DLBCL.
In this work, I was able to show that FOXP1 represses the transcription of the sphingosine 1-phosphate receptor 2 (S1PR2) gene. Moreover, expression of FOXP1 and S1PR2 negatively correlate in DLBCL patients and expression of S1PR2 harbors prognostic information for DLBCL patients. Over-expression of S1PR2 led to the induction of apoptosis in DLBCL cell lines and inhibited tumor growth in vitro and in vivo. I was further able to show that the induction of apoptosis by over-expressing S1PR2 was mediated by the downstream G-protein Gα13. S1PR2 and GNA13 are co- expressed in normal B-cell subsets and were previously demonstrated as frequently mutated in GCB-DLBCL patients, confirming their pivotal roles as tumor suppressor genes in DLBCL.

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Additional indexing

Item Type:Dissertation
Referees:Müller Anne, Hottiger M O, Christofori Gerhard, Tzankov Alexandar
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2016
Deposited On:28 Jan 2016 10:55
Last Modified:08 Dec 2017 18:06

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