SFPQ-ABL1 and BCR-ABL1 utilize different signalling networks to drive B-cell acute lymphoblastic leukaemia
- Author(s)
- Brown, LM; Hediyeh-Zadeh, S; Sadras, T; Huckstep, H; Sandow, JJ; Bartolo, RC; Kosasih, HJ; Davidson, N; Schmidt, BM; Bjelosevic, S; Johnstone, RW; Webb, AI; Khaw, SL; Oshlack, A; Davis, MJ; Ekert, PG;
- Journal Title
- Blood Advances
- Publication Type
- epub ahead of print
- Abstract
- Philadelphia-like (Ph-like) acute lymphoblastic leukaemia (ALL) is a high-risk subtype of B-cell ALL characterised by a gene expression profile resembling Philadelphia Chromosome positive ALL (Ph+ ALL) in the absence of BCR-ABL1. Tyrosine kinase activating fusions, some involving ABL1, are recurrent drivers of Ph-like ALL and are targetable with tyrosine kinase inhibitors (TKIs). We identified a rare instance of SFPQ-ABL1 in a child with Ph-like ALL. SFPQ-ABL1 expressed in cytokine-dependent cell lines was sufficient to transform cells which were sensitive to ABL1-targeting TKIs. 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. SFPQ-ABL1 was sensitive to navitoclax and S-63845 and promotes cell survival by maintaining expression of Mcl-1 and Bcl-xL. 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.
- Research Division(s)
- Bioinformatics; Advanced Technology And Biology; Blood Cells And Blood Cancer
- PubMed ID
- 35061886
- Publisher's Version
- https://doi.org/10.1182/bloodadvances.2021006076
- Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2021006076- Terms of Use/Rights Notice
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Creation Date: 2022-02-18 11:34:13
Last Modified: 2022-02-18 03:06:22