Guy Chowers1, Gadi Abebe-Campino2,3, Hana Golan2,3, Asaf Vivante1,2,4, Shoshana Greenberger2,5, Michalle Soudack6, Galia Barkai2,7, Ilana Fox-Fisher8, Dong Li9, Michael March9, Mark R Battig9, Hakon Hakonarson9,10,11, Denise Adams12, Yoav Dori10,13, Adi Dagan14,15,16. 1. Pediatrics B, Edmond and Lili Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. 2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3. Pediatric Hematology Oncology division, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. 4. Pediatric Nephrology Unit, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. 5. Pediatric Dermatology Unit, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. 6. Pediatric Imaging Unit, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. 7. Pediatric Infectious Diseases Unit, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. 8. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. 9. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 10. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 11. Divisions of Human Genetics and Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 12. Comprehensive Vascular Anomalies Program, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA. 13. Jill and Mark Fishman Center for Lymphatic Disorders, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 14. Pediatrics B, Edmond and Lili Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. daganay@gmail.com. 15. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. daganay@gmail.com. 16. Pediatric Pulmonary Unit and the National Center for Cystic Fibrosis, Edmond and Lili Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel. daganay@gmail.com.
Abstract
BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy. METHODS: The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay. RESULTS: Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib. CONCLUSIONS: Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies. IMPACT: This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.
BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy. METHODS: The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay. RESULTS: Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib. CONCLUSIONS: Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies. IMPACT: This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.
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