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Strong FOXP1 protein expression is a poor risk factor in diffuse large B-cell lymphoma and has been linked to an activated B-cell-like subtype, which preferentially expresses short FOXP1 (FOXP1S) proteins. However, both short isoform generation and function are incompletely understood. Here we prove by mass spectrometry and N-terminal antibody staining that FOXP1S proteins in activated B-cell-like diffuse large B-cell lymphoma are N-terminally truncated. Furthermore, a rare strongly FOXP1-expressing population of normal germinal center B cells lacking the N-terminus of the regular long protein (FOXP1L) was identified. Exon-targeted silencing and transcript analyses identified three alternate 5' non-coding exons [FOXP1-Ex6b(s), FOXP1-Ex7b and FOXP1-Ex7c], downstream of at least two predicted promoters, giving rise to FOXP1S proteins. These were differentially controlled by B-cell activation and methylation, conserved in murine lymphoma cells, and significantly correlated with FOXP1S protein expression in primary diffuse large B-cell lymphoma samples. Alternatively spliced isoforms lacking exon 9 (e.g. isoform 3) did not encode FOXP1S, and an alternate long human FOXP1 protein (FOXP1AL) likely generated from a FOXP1-Ex6b(L) transcript was detected. The ratio of FOXP1L:FOXP1S isoforms correlated with differential expression of plasmacytic differentiation markers in U-2932 subpopulations, and altering this ratio was sufficient to modulate CD19 expression in diffuse large B-cell lymphoma cell lines. Thus, the activity of multiple alternate FOXP1 promoters to produce multiple protein isoforms is likely to regulate B-cell maturation.

Original publication

DOI

10.3324/haematol.2016.142141

Type

Journal article

Journal

Haematologica

Publication Date

07/2016

Volume

101

Pages

861 - 871

Addresses

Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Oxford University, London, UK.

Keywords

B-Lymphocytes, Cell Line, Tumor, Animals, Humans, Mice, Protein Isoforms, Repressor Proteins, RNA, Messenger, Antigens, CD19, Lymphocyte Activation, Gene Expression Regulation, Neoplastic, Alternative Splicing, Exons, Forkhead Transcription Factors, Lymphoma, Large B-Cell, Diffuse, Protein Interaction Domains and Motifs, Promoter Regions, Genetic