Constant Activation of the RAF-MEK-ERK Pathway As a Diagnostic and Therapeutic Target in Hairy Cell Leukemia.

Abstract 2657 The BRAF-V600E mutation defines genetically hairy cell leukemia (HCL) among B-cell leukemias and lymhphomas. 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 of melanoma patients. However, the MEK-ERK pathway status in HCL has not been thoroughly investigated so far. Therefore, as a read-out of MEK-ERK pathway activation, we assessed phospho-ERK expression in 37 HCL patients using immunohistochemistry on routine biopsies and/or Western blotting on purified leukemic cells. Beside confirming the constant presence of BRAF-V600E in all patients, we documented ubiquitous phospho-ERK expression in HCL. Conversely, all 44 HCL-like cases in parallel studied (40 splenic marginal zone lymphoma, 2 HCL-variant and 2 splenic lymphoma/leukemia unclassifiable) were devoid of BRAF-V600E and none expressed phospho-ERK. Lack of phospho-ERK expression was also documented in two exceptionally rare cases of non-HCL CD5-negative B-cell lymphoproliferative disorders not otherwise specifiable that were previously described to harbour the BRAF-V600E mutation on allele-specific PCR (Arcaini et al, Blood 2012;119:188–191), pointing to the presence of this mutation in only a small part of the leukemic clone in these cases. Our findings support the use of phospho-ERK immunohistochemistry in the differential diagnosis between HCL and HCL-like neoplasms and establish the MEK-ERK pathway as a rational therapeutic target in HCL. Disclosures: Tiacci: Not applicable: Dr. Tiacci filed a patent for the clinical use of BRAF mutations as biomarkers of HCL. Other. Inghirami: OncoEthix SA: Research Funding. Falini: Not applicable: Dr. Falini filed a patent for the clinical use of BRAF mutations as biomarkers of HCL. Other.