IntroductionB-cell chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western hemisphere. It is characterized by the progressive accumulation of mature monoclonal CD5 ϩ B cells, which typically express low levels of surface immunoglobulin M (IgM) or IgM/IgD. The clinical course and outcome of CLL is variable. Some patients progress rapidly and die early in spite of therapy, whereas others exhibit a stable disease and a normal life span. 1 Recent studies have indicated that the B-cell receptor (BCR) is a major determinant of the clinical course in CLL. [2][3][4][5] The surface immunoglobulin (Ig) component of the BCR in patients with progressive disease is usually encoded by unmutated variable heavy-chain (V H ) region genes and associates with the T-cellspecific protein tyrosine kinase zeta-associated protein 70 . [3][4][5][6][7][8][9] In contrast, CLL B cells from patients with stable disease usually express IgM encoded by mutated Ig V H genes and do not express ZAP-70. Moreover, analysis of early signaling events induced by IgM ligation indicate that the 2 subsets may also differ in their capacity to transmit BCR-derived stimuli. [9][10][11] The BCR is a key signaling molecule that triggers pathways that can induce B-cell proliferation, survival, differentiation, anergy, and apoptosis (for a review, see Niiro and Clark 12 ). In normal B cells, stimulation of the BCR leads to phosphorylation of immunoreceptor tyrosine-based activation motifs within the cytoplasmic tails of Ig␣ and Ig␤. The protein tyrosine kinase Syk is subsequently recruited to these motifs and becomes activated, initiating activation of the crucial effector enzymes phosphatidyl 3-kinase (PI3K) and phospholipase C␥2 (PLC␥2). PI3K generates the key second messenger phosphatidylinositol-3,4,5-triphosphate, which recruits other BCR signaling molecules to the membrane and activates the downstream kinase Akt. The PI3K/Akt pathway plays an important role in promoting B-cell survival and protecting against BCR-induced cell death by inducing the expression of antiapoptotic proteins, such as myeloid cell leukemia-1 (Mcl-1) and X-linked inhibitor of apoptosis protein (XIAP), and inactivating cellular targets involved in the induction of apoptosis, such as BAD (Bcl 2 antagonist of cell death) and caspase-9. [13][14][15][16] Activation of PLC␥2 leads to the release of intracellular Ca 2ϩ and activation of protein kinase C (PKC), which are crucial for the activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), c-JUN NH 2 -terminal kinase (JNK), and p38 MAPK, and transcription factors, including nuclear factor-B (NF-B) and nuclear factor of activated T cells (NFAT). The balance of these signaling molecules subsequently determines B-cell fate. However, in terms of their individual activity, NF-B appears to play a prominent role in the survival of antigenstimulated B cells by inducing the expression of several antiapoptotic proteins, such as B-cell leukemia/lymphoma 2 (Bcl-2), Bcl-...

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