Activating MAPK1 (ERK2) mutation in an aggressive case of disseminated juvenile xanthogranuloma

// Rikhia Chakraborty 1, 2 , Oliver A. Hampton 3, 5 , Harshal Abhyankar 1, 2 , Daniel J. Zinn 1, 2 , Amanda Grimes 1, 2 , Brooks Skull 1, 2 , Olive Eckstein 1, 2 , Nadia Mahmood 6 , David A. Wheeler 3, 5 , Dolores Lopez-Terrada 1, 4 , Tricia L. Peters 4 , John M. Hicks 4 , Tarek Elghetany 4 , Robert Krance 1, 2, 7 , Poulikos I. Poulikakos 8, 9, 10 , Miriam Merad 8, 9, 11 , Kenneth L. McClain 1, 2 , Carl E. Allen 1, 2 and Donald W. Parsons 1, 2, 3, 4, 5 1 Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX 77030, USA 2 Department of Pediatrics, Division of Pediatric Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030, USA 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 4 Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA 5 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA 6 Body and Nuclear Radiology Sections, Texas Children’s Hospital, Houston, TX 77030, USA 7 Center for Cell and Gene Therapy, Houston, TX 77030, USA 8 Department of Oncological Sciences, Icahn School of Medicine, New York, NY 10029, USA 9 Tisch Cancer Institute, Icahn School of Medicine, New York, NY 10029, USA 10 Immunology Institute, Icahn School of Medicine, New York, NY 10029, USA 11 Department of Dermatology, Icahn School of Medicine, New York, NY 10029, USA Correspondence to: Donald W. Parsons, email: dwparson@txch.org Carl E. Allen, email: ceallen@txch.org Keywords: juvenile xanthogranuloma, MAPK1 , ERK activation, histiocytic disorder, somatic mutation Received: October 13, 2016      Accepted: March 13, 2017      Published: April 29, 2017 ABSTRACT Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder that is usually benign and self-limiting. We present a case of atypical, aggressive JXG harboring a novel mitogen-activated protein kinase (MAPK) pathway mutation in the MAPK1 gene, which encodes mitogen-activated protein kinase 1 or extracellular signal-regulated 2 (ERK2). Our analysis revealed that the mutation results in constitutive ERK activation that is resistant to BRAF or MEK inhibitors but susceptible to an ERK inhibitor. These data highlight the importance of identifying specific MAPK pathway alterations as part of the diagnostic workup for patients with histiocytic disorders rather than initiating empiric treatment with MEK inhibitors.