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06 January 2017

Scientists have discovered new gene mutations that are linked to drug resistance in childhood T-cell acute lymphoblastic leukaemia.

This finding could help explain, and possibly avoid, the treatment resistance which is so detrimental to some patients.

Dr Jules Meijerink of the Princess Maxima Centre for Pediatric Oncology, Utrecht, The Netherlands and colleagues combined several genomic datasets to study changes in leukaemic cells at diagnosis, before treatment with commonly-used steroid drugs.

They discovered specific gene mutations that affect signalling inside cells and are associated with steroid resistance and adverse clinical outcome. These mutations involve the interleukin 7 receptor and associated molecules.

Next, the team used cells from patients with T-cell acute lymphoblastic leukaemia and treated them either with steroids alone, or alongside interleukin 7 inhibitors. They found that including these inhibitors significantly enhanced steroid-induced cell death. Full steroid sensitivity was restored in the leukaemic cells.

Full details appeared in PLoS Medicine. They write: "Treatment success and clinical outcome are highly dependent on steroid sensitivity in this setting."

Commenting on the findings, Dr Steven Goossens and Pieter Van Vlierberghe of Ghent University Hospital, Belgium, suggest that inhibition of certain gene signalling, such as MEK-ERK or PI3K/AKT/mTOR, "could enhance steroid sensitivity in T-cell acute lymphoblastic leukaemia and potentially improve patient outcomes, a notion that warrants investigation in future prospective clinical trials.

"Ultimately, these efforts should improve clinical outcome in T-cell acute lymphoblastic leukaemia and reduce the detrimental toxic side-effects associated with high-dose chemotherapy," they write.

Source: Li, Y. et al. IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study. PLoS Medicine 20 December 2016; doi:10.1371/journal.pmed.1002200

Link: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.100



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