title: The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells.
abstract: The forkhead transcription factor FOXP1 is generally regarded as an oncogene in activated B cell-like diffuse large B-cell lymphoma. Previous studies have suggested that a small isoform of FOXP1 rather than full-length FOXP1, may possess this oncogenic activity. Corroborating those studies, we herein show that activated B cell-like diffuse large B-cell lymphoma cell lines and primary activated B cell-like diffuse large B-cell lymphoma cells predominantly express a small FOXP1 isoform, and that the 5'-end of theFoxp1gene is a common insertion site in murine lymphomas in leukemia virus- and transposon-mediated insertional mutagenesis screens. By combined mass spectrometry, (quantative) reverse transcription polymerase chain reaction/sequencing, and small interfering ribonucleic acid-mediated gene silencing, we determined that the small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma lacks the N-terminal 100 amino acids of full-length FOXP1. Aberrant overexpression of this FOXP1 isoform (ΔN100) in primary human B cells revealed its oncogenic capacity; it repressed apoptosis and plasma cell differentiation. However, no difference in potency was found between this small FOXP1 isoform and full-length FOXP1. Furthermore, overexpression of full-length FOXP1 or this small FOXP1 isoform in primary B cells and diffuse large B-cell lymphoma cell lines resulted in similar gene regulation. Taken together, our data indicate that this small FOXP1 isoform and full-length FOXP1 have comparable oncogenic and transcriptional activity in human B cells, suggesting that aberrant expression or overexpression of FOXP1, irrespective of the specific isoform, contributes to lymphomagenesis. These novel insights further enhance the value of FOXP1 for the diagnostics, prognostics, and treatment of diffuse large B-cell lymphoma patients.
authors.affiliation: Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Leiden University Medical Center, Amsterdam, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: van Keimpema
authors.affiliation: Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Leiden University Medical Center, Amsterdam, The Netherlands.
authors.forename: Leonie J
authors.initials: LJ
authors.lastname: Grüneberg
authors.affiliation: Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Leiden University Medical Center, Amsterdam, The Netherlands.
authors.forename: Esther J M
authors.initials: EJ
authors.lastname: Schilder-Tol
authors.affiliation: Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Leiden University Medical Center, Amsterdam, The Netherlands.
authors.forename: Monique E C M
authors.initials: ME
authors.lastname: Oud
authors.affiliation: Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Leiden University Medical Center, Amsterdam, The Netherlands.
authors.forename: Esther A
authors.initials: EA
authors.lastname: Beuling
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Amsterdam, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hensbergen
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer institute, Amsterdam, The Netherlands.
authors.forename: Johann
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Leiden University Medical Center, Amsterdam, The Netherlands.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals
authors.affiliation: Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Leiden University Medical Center, Amsterdam, The Netherlands marcel.spaargaren@amc.uva.nl.
authors.forename: Marcel
authors.initials: M
authors.lastname: Spaargaren
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016254:Mutagenesis, Insertional; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020033:Protein Isoforms; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D012097:Repressor Proteins; D053148:Caspase 3; D053179:Caspase 7