Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition.

Autor: Sheppard SE; Center for Applied Genomics.; Division of Human Genetics, and., March ME; Center for Applied Genomics., Seiler C; Zebrafish Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Matsuoka LS; Center for Applied Genomics., Kim SE; Center for Applied Genomics., Kao C; Center for Applied Genomics., Rubin AI; Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Battig MR; Center for Applied Genomics., Khalek N; Richard D. Wood Jr. Center for Fetal Diagnosis and Treatment and., Schindewolf E; Richard D. Wood Jr. Center for Fetal Diagnosis and Treatment and., O'Connor N; Center for Applied Genomics., Pinto E; Jill and Mark Fishman Center for Lymphatic Disorders, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Priestley JR; Division of Human Genetics, and., Sanders VR; Division of Human Genetics, and., Niazi R; Genetic Diagnostic Laboratory, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Ganguly A; Genetic Diagnostic Laboratory, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Hou C; Center for Applied Genomics., Slater D; Center for Applied Genomics., Frieden IJ; Department of Dermatology and., Huynh T; Department of Dermatology and., Shieh JT; Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA., Krantz ID; Division of Human Genetics, and.; Roberts Individualized Medical Genetics Center, Division of Human Genetics., Guerrero JC; Department of Pathology., Surrey LF; Department of Pathology., Biko DM; Department of Radiology., Laje P; Department of Surgery; and., Castelo-Soccio L; Dermatology Section, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Nakano TA; Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado, USA., Snyder K; Division of Oncology, Cancer Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Smith CL; Jill and Mark Fishman Center for Lymphatic Disorders, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Li D; Center for Applied Genomics., Dori Y; Jill and Mark Fishman Center for Lymphatic Disorders, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Hakonarson H; Center for Applied Genomics.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2023 May 08; Vol. 8 (9). Date of Electronic Publication: 2023 May 08.
DOI: 10.1172/jci.insight.155888
Abstrakt: Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.
Databáze: MEDLINE
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