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that are relevant to the pathogenesis of HCL. A minority of cases are unmutated (UM-HCL) [22] and apparently more responsive to BCR triggering, whereas the BCR of M-HCL may be less sensitive to stimulation by antigen [22]. The issue becomes how we might translate these BCR-related insights into therapeutic approaches. The possibility of targeting signal transduction pathways activated in HCs by microenvironmental interactions that activate the BCR exists, considering the impressively rapid progress in the field of BCR-related signaling inhibitors. In patients with CLL, inhibition of BCR signaling is currently emerging as a promising new therapeutic approach, using specific spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (Btk), or phosphatidylinositol 3-kinase (PI3K) inhibitors. This raises the question whether subgroups of patients with HCL, such as those with UM-HCL, may be candidates for alternative treatments with these new, targeted agents.
T cell interactions with hairy cells
Immunodeficiency in patients with HCL is thought to be related, at least in part, to T cell dysfunction [28,29]. Interestingly, T cells from the blood and spleen of most patients with HCL are clonally expanded and show a restricted and skewed reper- toire of the T-cell receptor b family [30], suggesting activation and expansion of oligoclonal T cells in response to the HCL clone. Such T cells can recognize and then become activated by autologous, CD40-activated HCs [31]. The key question remains whether such HC-reactive T cells suppress or stimulate the HCL clone. The fact that CD40 crosslinking is a very potent stimulus for HC proliferation [32] indicates that interactions between HCs and CD40 ligand (CD154) expressing T cells in tissue microenvironments would result in disease progression, rather than suppression (Figure 2).
Targeting the microenvironment in hairy cell leukemia: CXCR4 and B cell receptor signaling
Overall, we are only starting to learn which pathways deliver critical survival and drug-resistance signals in the complex interactions that occur between mature B-cell malignancies and their microenvironments [2]. In this context the bone marrow is a tissue of crucial importance, given that the marrow is a common site of minimal residual disease (MRD) and the source of relapses in patients with B-cell tumors such as HCL. One possible explanation is that, while conventional treatment eliminates the bulk of clonal elements, residual HCs lurk in protective niches where they receive signals from
accessory cells that promote survival and drug- resistance. It is reasonable to suggest that these niches may have similarities with niches that nor- mally protect hematopoietic progenitors, including the presence of stromal cells, T cells, and endothelial cells [20]. Given the importance of CXCR4 for malignant B-cell adhesion to MSCs [33], and more generally, its significance for cancer stem cell homing to protective niches [34], CXCR4 antagonists (Plerixafor/AMD3100, or T140 analogs) could be useful for mobilizing HCs for a more effective exposure to anticancer drugs. However, this ap- proach would also co-mobilize normal hematopoietic progenitor cells and expose them to cytotoxic drugs outside their protective niches, which might result in increased toxicity. Ongoing and future clinical trials using CXCR4 antagonists will have to determine whether malignant B-cells have the same mobiliza- tion threshold as normal stem cells. Combinations of CXCR4 antagonists with drugs that target predomi- nantly the malignant cells, such as anti-CD20 monoclonal antibodies, could help avoid this poten- tial hazard. An alternative, similarly exciting therapeutic
approach is related to BCR signaling. BCR signaling is increasingly recognized as a central patho-mechanism in B-cell malignancies, including CLL [21,35] and diffuse large B-cell lymphoma (DLBCL) [36]. New targeted agents that interfere with BCR signaling, such as Syk and Btk inhibi- tors, are entering the clinical stage and show promising results in first clinical trials in patients with CLL and other B-cell malignancies [37,38]. Because of these emerging new therapeutic options it is important to identify patients who may benefit from these new approaches and/or become candi- dates for treatment at an early stage of their disease. Some data suggest that UM-HCL cells are more responsive to BCR stimulation [22] and hence could be more responsive to therapeutic approaches targeting the BCR. Collectively, new therapeutic approaches that
target the cross-talk between HCL cells and their microenvironment, rather than the HCs alone, could become a clinical reality in the near future. Targeting either CXCR4 chemokine receptor or BCR signaling could be explored in HCL, given that effective agents are already in clinical use in patients with other B-cell malignancies. The question will become how to best explore the activity of these drugs (i.e. in untreated or treated patients, alone or in combination with standard therapy, or for treatment of residual disease). After establishment of purine nucleoside analogs as standard therapy for HCL, such disease biology-oriented approaches are the next logical step for improving the outcome in HCL. Hopefully, such
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