SFPQ-ABL1 and BCR-ABL1 utilise different signalling networks to drive B-cell acute lymphoblastic leukaemia

ABSTRACT: Purpose: We identified a rare instance of the SFPQ-ABL1 in a child with Ph-like ALL. The overall purpose of this study was to compare the structure and function of the SFPQ-ABL1 fusion to the well characterised BCR-ABL1 fusion. We used phosphoproteomics, transcriptomics and functional assays to determine the transforming capacity, subcellular localisation, and signalling networks of these two fusions. Given the known function of SFPQ in mRNA splicing, transcriptomic analysis was performed to analyse the effect of BCR-ABL1 or SFPQ-ABL1 expression on gene splicing. Methods: mRNA profiles of Ba/F3 cells expressing BCR-ABL1, SFPQ-ABL1, and empty vector control (MSCV) were generated by deep sequencing, in four biologically independent cell lines, using Illumina GAIIx. The sequences were aligned by subread and quantified by featureCounts. Results: In contrast to BCR-ABL1, SFPQ-ABL1 localised to the nuclear compartment and was a weaker driver of cellular proliferation. Phosphoproteomics analysis showed upregulation of cell cycle, DNA replication and spliceosome pathways, and downregulation of signal transduction pathways, including ErbB, NF-kappa B, VEGF, and MAPK signalling in SFPQ-ABL1-, compared to BCR-ABL1-expressing cells. SFPQ-ABL1 expression did not activate PI3K/AKT signalling and was associated with phosphorylation of G2/M cell cycle proteins. We identified no difference in overall splicing between cells expressing BCR-ABL1 and SFPQ-ABL1. Conclusions: SFPQ-ABL1 has functionally distinct mechanisms by which it drives ALL, including subcellular localisation, proliferative capacity, and activation of cellular pathways, highlighting the role that fusion partners have in mediating the function of ABL1 fusions.

ORGANISM(S): Mus musculus

PROVIDER: GSE185860 | GEO | 2021/10/15

REPOSITORIES: GEO