Fig. 1.

Mechanism of action of currently used therapies and potential therapeutic targets in hairy cell leukemia (HCL). Intracellular signaling pathways in HCL B cells are shown. B-cell receptor (BCR) and Raf-MEK/ERK signaling are the dominant pathways with major therapeutic implications in HCL. The pink lightning bolt symbol indicates therapeutic targets. (a) Purine analogues (shown in dark green). Purine analogues are the most commonly used chemotherapeutic agents in HCL. Cladribine and pentostatin inhibit DNA polymerase and adenosine deaminase, prevent DNA repair, and promote DNA damage. (b) Monoclonal antibodies (mAbs) and immunotoxins (shown in yellow). HCL B cells overexpress CD20, CD22, and CD25. These are the common surface epitopes exploited for therapy. Rituximab is an anti-CD20 mAb. Immunotoxins against CD22 and CD25 are in clinical trials. Recombinant immunotoxins combine the binding domain of the plant or the bacterial toxin with the variable region of the mAb. These agents facilitate the entry of an exogenous toxin into the cell cytoplasm, block protein synthesis, and inhibit rough endoplasmic reticulum by ribosylation of the elongation factor. Examples of immunotoxins are BL22 (anti-CD22 mAb fused to pseudomonas exotoxin PE38) and HA22 (moxetumomab pasudotox). (c) Inhibitors of BCR signaling (shown in white). BCR is composed of two immunoglobulin heavy and light chains (variable and constant regions) and CD79a, which have an intracellular activation motif that transmits signals to intracellular tyrosine kinases (e.g., Btk, Syk, and Lyn). A Btk inhibitor (ibrutinib) is the most promising treatment for HCL and is currently under evaluation. (d and e) Inhibitors of Raf-MEK/ERK. Mutations of BRAF (V600E) are considered a major factor for HCL cell growth. Raf-MEK/ERK signaling pathways can be blocked by inhibition of BRAF (shown in light green) by agents such as vemurafenib or by inhibition of mitogen-activated kinase (MEK) by trematinib (shown in blue).