Editors' ChoiceCancer

Everything you splice can and will be used against you

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Science Translational Medicine  21 Sep 2016:
Vol. 8, Issue 357, pp. 357ec151
DOI: 10.1126/scitranslmed.aah7025

Age-related human hematopoietic stem and progenitor cell (HSPC) exhaustion and myeloid-skewed hematopoiesis are associated with an increased risk of myelodysplastic syndrome (MDS) and leukemic transformation. Secondary acute myeloid leukemia (AML) that evolved from prior MDS carries mutations in genes encoding the RNA processing machinery, but how alternative RNA splicing distinguishes aging HSPCs from leukemic stem cells (LSCs) and whether modulation of RNA splicing could sensitize LSCs to therapies have not been determined. Using RNA sequencing (RNA-seq) and splice isoform-specific PCR, Crews et al. uncovered RNA splice isoform signatures that distinguish normal young and old HSPC from their malignant counterparts.

By comparing transcriptomes and splice isoform profiles of normal young and old HSPC, the authors first showed that differential splicing regulation, epigenetic regulation and inflammation pathways are associated with HSPC aging. By performing RNA-seq of flow cytometry purified secondary AML progenitors they identified the spliceosome as the most commonly disrupted gene set compared with normal progenitors. Pathway-specific analyses showing that spliceosome disruption was associated with splicing alterations of stem cell regulatory genes, inflammatory genes, or anti-apoptosis genes allowed the authors to generate a splice isoform signature for LSC. This finding could be prognostically relevant because an unsupervised clustering analysis of datasets from the Cancer Gene Atlas showed 6 distinct subgroups based on splice isoform signatures, some of which were associated with a distinct overall survival advantage or disadvantage.

Last, the authors tested the hypothesis that LSC maintenance was dependent on the demonstrated aberrant splicing by treating patient-derived AML specimens with an inhibitor of the SF3B subunit of the spliceosome, 17S-FD-895. The authors were able to reverse the prosurvival splice isoform switching by triggering exon skipping in anti-apoptotic genes MCL1, BCL2L1, and BCL2. This selectively inhibited in vitro clonogenicity and self-renewal, as well as the in vivo serial transplantation potential of LSC, compared with that of normal HSPC in xenografted mice, presumably because of selective reliance by on the prosurvival signals. This study provides a proof-of-concept that the deleterious mutations that characterize some forms of AML can be used against them.

L. A. Crews et al., RNA splicing modulation selectively impairs leukemia stem cell maintenance in secondary human AML. Cell Stem Cell 10.1016/j.stem.2016.08.003 (2016). [Abstract]

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