RNA-binding proteins play a key role in sustaining drug-resistant leukaemia stem cells in aggressive myeloid disease, according to new findings.
The work was carried out by Professor Tannishtha Reya of the University of California San Diego School of Medicine, USA, and colleagues. They used CRISPR gene editing technology to find genes which regulate the blast crisis phase of chronic myeloid leukaemia (CML). They went on to focus on the RNA-binding protein Staufen2, which had been linked to brain and nervous system development.
Tests on mice showed that Staufen2 is a key protein that sustains and protects drug-resistant leukaemia stem cells. Mice with genetically-deleted Staufen2 showed a significant reduction in leukaemia cell growth and “markedly improved” overall survival. Tests on samples donated by human patients also suggest that Staufen2 is needed for leukaemia cell growth.
Full details appear in the journal Nature Cancer.
Prof Reya said: “The study shows, for the first time, that whole genome CRISPR-based screens can in fact be carried out in a manner that is much more physiologically relevant: using primary cancer cells, and in the setting of the native microenvironment.”
She added: “We are particularly excited about this work because, to our knowledge, this is the first demonstration that Staufen2 is a key dependency in any cancer.”
Dr Jeevisha Bajaj, lead author, commented: “This work will be particularly important for the discovery of new treatments.
“Our genome-wide screen identified cellular signals critical for the growth of cancer, and in the future, this study will be useful to study the microenvironment, the area around the tumour that includes tissue, blood vessels and important molecular signals related to how the cancer behaves.”
Source: Bajaj J, Hamilton M, Shima Y, Chambers K, Spinler K, Van Nostrand EL, Yee BA, Blue SM, Chen M, Rizzeri D, Chuah C, Oehler VG, Broome HE, Sasik R, Scott-Browne J, Rao A, Yeo GW, Reya T (2020) “An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia”, Nature Cancer, doi: 10.1038/s43018-020-0054-2
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