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,
Alejandra Martínez-Trillos,
Arnau Montraveta,
Mónica Lopez-Guerra,
Laia Rosich,
Ferran Nadeu,
Juan G. Valero,
Marta Aymerich,
Laura Magnano,
Maria Rozman,
Estella Matutes,
Julio Delgado,
Tycho Baumann,
Eva Gine,
Marcos González,
Miguel Alcoceba,
M. José Terol,
Blanca Navarro,
Enrique Colado,
Angel R. Payer,
Xose S. Puente,
Carlos López-Otín,
Armando Lopez-Guillermo,
Elias Campo,
Dolors Colomer,
Neus Villamor
Affiliations
Neus Giménez
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Anaxomics Biotech, Barcelona
Alejandra Martínez-Trillos
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Hematology Department
Arnau Montraveta
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona
Mónica Lopez-Guerra
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Hematopathology Unit, Hospital Clinic, Barcelona
Laia Rosich
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona
Ferran Nadeu
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona
Juan G. Valero
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona
Marta Aymerich
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Hematopathology Unit, Hospital Clinic, Barcelona
Laura Magnano
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Hematopathology Unit, Hospital Clinic, Barcelona
Maria Rozman
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Hematopathology Unit, Hospital Clinic, Barcelona
Estella Matutes
Hematopathology Unit, Hospital Clinic, Barcelona
Julio Delgado
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Hematology Department
Tycho Baumann
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Hematology Department
Eva Gine
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona;Hematology Department
Marcos González
Hematology Department, University Hospital- IBSAL, and Institute of Molecular and Cellular Biology of Cancer, University of Salamanca, CIBERONC
Miguel Alcoceba
Hematology Department, University Hospital- IBSAL, and Institute of Molecular and Cellular Biology of Cancer, University of Salamanca, CIBERONC
Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic 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 mutations 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 dehydrogenase 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 findings, 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 features and could be pharmacologically inhibited.