The leukemia cells of patients with chronic lymphocytic leukemia (CLL) are highly fastidious, requiring stimulation by soluble factors and interactions with accessory cells within the supportive niches of lymphoid tissue that comprise the leukemia microenvironment. The advent of therapies that can disrupt some of the stimulatory signaling afforded by the microenvironment has ushered in a new era of targeted therapy, which has dramatically improved clinical outcome and patient survival. Future advances are required for patients who develop intolerance or resistance to current targeted therapies. These may be found by investigating novel drugs that can inhibit identified targets, such as the pathways involved in B-cell receptor signaling, or by developing agents that inhibit additional targets of the leukemia microenvironment. This review describes some of the molecules involved in promoting the growth and/or survival of CLL cells and discusses targeting strategies that may become tomorrow's therapy for patients with CLL.
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