Constant activation of the RAF-MEK-ERK pathway as a diagnostic and therapeutic target in hairy cell leukemia.
The BRAF-V600E mutation defines genetically hairy cell leukemia among B-cell leukemias and lymphomas. In solid tumors, BRAF-V600E is known to aberrantly activate the oncogenic MEK-ERK pathway, and targeted BRAF and/or MEK inhibitors have shown remarkable efficacy in clinical trials in melanoma patients. However, the MEK-ERK pathway status in hairy cell leukemia has not been thoroughly investigated. We assessed phospho-ERK expression in 37 patients with hairy cell leukemia and 44 patients with neoplasms mimicking hairy cell leukemia (40 splenic marginal zone lymphoma, 2 hairy cell leukemia-variant and 2 splenic lymphoma/leukemia unclassifiable) using immunohistochemistry on routine biopsies and/or Western blotting on purified leukemic cells, and correlated the phospho-ERK status with the BRAF-V600E mutation status. Besides confirming the constant presence of BRAF-V600E in all patients with hairy cell leukemia, we observed ubiquitous phospho-ERK expression in this malignancy. Conversely, all 44 cases with neoplasms mimicking hairy cell leukemia were devoid of BRAF-V600E and none expressed phospho-ERK. Furthermore, the two exceptionally rare cases of non-hairy cell leukemia unclassifiable chronic B-cell neoplasms previously reported to be BRAF-V600E(+) on allele-specific polymerase chain reaction lacked phospho-ERK expression as well, suggesting the presence of the mutation in only a small part of the leukemic clone in these cases. In conclusion, our findings support the use of phospho-ERK immunohistochemistry in the differential diagnosis between hairy cell leukemia and its mimics, and establish the MEK-ERK pathway as a rational therapeutic target in this malignancy.
Institute of Hematology, Ospedale S. Maria della Misericordia, University of Perugia, Perugia, Italy. etiacci@solido.umbria.it
Enrico
E
Tiacci
Gianluca
G
Schiavoni
Maria Paola
MP
Martelli
Emanuela
E
Boveri
Roberta
R
Pacini
Alessia
A
Tabarrini
Silvia
S
Zibellini
Alessia
A
Santi
Valentina
V
Pettirossi
Elisabetta
E
Fortini
Stefano
S
Ascani
Luca
L
Arcaini
Giorgio
G
Inghirami
Marco
M
Paulli
Brunangelo
B
Falini
D019943:Amino Acid Substitution; D018951:Antigens, CD20 / Q000378:metabolism; D015153:Blotting, Western; D003937:Diagnosis, Differential; D006801:Humans; D007150:Immunohistochemistry; D007943:Leukemia, Hairy Cell / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
D018951:Antigens, CD20; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3