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Haematologica 2019 Volume 104(3):576-586
Chronic Lymphocytic Leukemia
Mutations in the RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
Neus Giménez,1,2* Alejandra Martínez-Trillos,1,3* Arnau Montraveta,1 Mónica
Lopez-Guerra,1,4 Laia Rosich,1 Ferran Nadeu,1 Juan G. Valero,1 Marta
Aymerich,1,4 Laura Magnano,1,4 Maria Rozman,1,4 Estella Matutes,4 Julio
1,3 1,3 1,3 5 5 Delgado, Tycho Baumann, Eva Gine, Marcos González, Miguel Alcoceba,
M. José Terol,6 Blanca Navarro,6 Enrique Colado,7 Angel R. Payer,7 Xose S. Puente,8 Carlos López-Otín,8 Armando Lopez-Guillermo,1,3 Elias Campo,1,4 Dolors Colomer1,4** and Neus Villamor1,4**
1Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona; 2Anaxomics Biotech, Barcelona; 3Hematology Department and 4Hematopathology Unit, Hospital Clinic, Barcelona; 5Hematology Department, University Hospital- IBSAL, and Institute of Molecular and Cellular Biology of Cancer, University of Salamanca, CIBERONC; 6Hematology Department, Hospital Clínico Universitario, Valencia: 7Hematology Department, Hospital Universitario Central de Asturias, Oviedo, and 8Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, CIBERONC, Spain.
*NG and AM-T contributed equally to the study.
**DC and NV share senior authorship of the manuscript.
ABSTRACT
Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lym- phocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the in vitro response of primary cells to BRAF and ERK inhibitors. Putative damaging muta- tions were found in 25 of 452 patients (5.5%). Among these, BRAF was mutated in nine patients (2.0%), genes upstream of BRAF (KITLG, KIT, PTPN11, GNB1, KRAS and NRAS) were mutated in 12 patients (2.6%), and genes downstream of BRAF (MAPK2K1, MAPK2K2, and MAPK1) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydro- genase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, P=0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these find- ings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical fea- tures and could be pharmacologically inhibited.
Correspondence:
DOLORS COLOMER
dcolomer@clinic.cat
Received: May 1, 2018.
Accepted: September 26, 2018. Pre-published: September 27, 2018.
doi:10.3324/haematol.2018.196931
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/576
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