Diverse and targetable kinase alterations drive histiocytic neoplasms

Eli L. Diamond, Benjamin H. Durham, Julien Haroche, Zhan Yao, Jing Ma, Sameer A. Parikh, Zhaoming Wang, John Choi, Eunhee Kim, Fleur Cohen-Aubart, Stanley Chun Wei Lee, Yijun Gao, Jean Baptiste Micol, Patrick Campbell, Michael P. Walsh, Brooke Sylvester, Igor Dolgalev, Olga Aminova, Adriana Heguy, Paul ZappileJoy Nakitandwe, Chezi Ganzel, James D. Dalton, David W. Ellison, Juvianee Estrada-Veras, Mario Lacouture, William A. Gahl, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, Siraj M. Ali, Samuel R. Briggs, Omotayo Fasan, Jared Block, Sebastien Heritier, Jean Donadieu, David B. Solit, David M. Hyman, Jose Baselga, Filip Janku, Barry S. Taylor, Christopher Y. Park, Zahir Amoura, Ahmet Dogan, Jean Francois Emile, Neal Rosen, Tanja A. Gruber, Omar Abdel-Wahab

Research output: Contribution to journalArticlepeer-review

209 Scopus citations


Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non- LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1 - and ARAF -mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.SIGNIFICANCE: We provide the fi rst description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1 - and ARAF -mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.

Original languageEnglish (US)
Pages (from-to)154-165
Number of pages12
JournalCancer discovery
Issue number2
StatePublished - Feb 2016

ASJC Scopus subject areas

  • Oncology


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