The Biology of Classic Hairy Cell Leukemia

Abstract

Classic hairy cell leukemia (HCL) is a rare mature B-cell malignancy associated with pancytopenia and infectious complications due to progressive infiltration of the bone marrow and spleen. Despite tremendous therapeutic advances achieved with the implementation of purine analogues such as cladribine into clinical practice, the culprit biologic alterations driving this fascinating hematologic disease have long stayed concealed. Nearly 10 years ago, BRAF V600E was finally identified as a key activating mutation detectable in almost all HCL patients and throughout the entire course of the disease. However, additional oncogenic biologic features seem mandatory to enable HCL transformation, an open issue still under active investigation. This review summarizes the current understanding of key pathogenic mechanisms implicated in HCL and discusses major hurdles to overcome in the context of other BRAF-mutated malignancies.

Keywords: B-cell receptor; BRAF V600E; DUSP; HCL; JNK; biology; epigenetic; fibronectin; hairy cell leukemia; methylome; microRNA; microenvironment; p38; single-cell sequencing; vitronectin.

Figure 1

Current understanding of classic hairy cell leukemia biology. Line arrows with thunder illustrate evasion from pro-apoptotic signaling pathways; Dash arrows show proposed signaling outputs of constitutive ERK-signaling derived from preclinical data in BRAF-mutant melanoma cell lines; BRAF V600E, driver mutation in HCL; BCR, B-cell receptor; bFGF, basic fibroblast growth factor; BMSC, mesenchymal bone marrow stromal cells; BTK, Bruton’s tyrosine kinase; CXCL12, C-X-C motif chemokine 12; CXCR4, C-X-C chemokine receptor 4; DUSP, dual specificity phosphatase; ERK, extracellular-signal regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; PKC, protein kinase C; PLCy, phospholipase C gamma; TGF, tumor growth factor; VCAM, vascular cell adhesion molecule; VLA, very late antigen, adhesion molecules.