A team of researchers, including our ‘own’ Michael Dellinger, Juan Carlos López-Guttiérrez and Victor Martínez-Glez, have published this outstanding article on GLA, formerly known as lymphangiomatosis.
Generalized lymphatic anomaly (GLA) is a vascular disorder
characterized by diffuse or multifocal lymphatic malformations (LMs). The
etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants
(Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five
out of nine patients with GLA. These same PIK3CA variants
occur in PIK3CA-related overgrowth
spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that
the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction
in mice that expressed an active form of PIK3CA (His1047Arg)
in their lymphatics. We also found that rapamycin reduced pain in patients with
GLA. In conclusion, we report that somatic activating PIK3CA mutations can
cause GLA, and we provide preclinical and clinical evidence to support the use
of rapamycin for the treatment of this disabling and deadly disease.
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version of this publication: DOI: 10.1084/jem.20181353. If this is not possible,
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