Chromosome 7 abnormalities - monosomy 7 and del(7q) - typically portend a dismal prognosis in myelodysplastic syndrome (MDS) and other bone marrow failure disorders – comprising one of the most common associated cytogenetic abnormalities. With no significant therapies to leverage the resulting haploinsufficiency to date, stem cell transplant remains the standard of care in spite of its inherent risks and costs at both the individual and institutional level. Spliceosome modulators have recently been developed and trialled in low-grade MDS patients with associated mutation of spliceosome components. The results to date have been modest at best.
In this context, we performed genome-wide CRISPR-based screening to identify factors that predict for sensitisation to these compounds. The multi-drug resistant exporter, MDR-1 or ABCB1 located on chromosome 7q.21 scored as one of the strongest sensitising hits for spliceosome modulator H3B-8800. On this basis, we hypothesized that haploinsufficiency at the ABCB1 locus as occurs in monosomy 7 and a subset of del(7q) patients may predict for increased sensitivity to this group of compounds due to increased drug retention. Knock-out of ABCB1 using CRISPR-Cas9 in a panel of leukaemic cell lines validated our screen findings - demonstrating increased sensitivity using cell proliferation and competition-based assays. Further generation and validation of cellular models of monosomy 7 is currently underway. If validated, these findings may uncover a therapeutic vulnerability rendering ABCB1-haploinsufficient cells more sensitive to compound. We will subsequently determine whether these findings can be extrapolated to other compounds that are exported via the same mechanism.