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Chapter 4Apoptosis Pathways in Chronic LymphocyticLeukemia: Role of the Microenvironmentand Therapeutic StrategiesViralkumar Patel, Kumudha Balakrishnan, and Varsha GandhiAbstract Chronic lymphocytic leukemia (CLL) is a B‐cell malignancy marked bydefective apoptosis and apoptotic resistance. CLL lymphocytes accumulate in bonemarrow, lymph nodes, and peripheral blood and receive survival signals through adiverse microenvironment in these body compartments. CLL microenvironmentand cell interactions have been studied extensively. The microenvironment aggra-vates the antiapoptotic components in CLL cells and depletes the proapoptoticsignaling that is essential to defending against apoptosis resistance. Ample researchhas been conducted to understand the involvement of apoptosis pathway proteinsand the role of the microenvironment in the biology of leukemic cells. Majorprotein groups of the apoptosis pathway are the B‐cell lymphoma 2 (Bcl-2) family,inhibitor of apoptosis protein (IAP) family, nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF-kB) signaling axis, tumor necrosis factor receptorsuperfamily (TNFRSF), B-cell receptor (BCR), death effector domain-containingproteins (DED) family, caspase activation and recruitment domain-containing pro-teins (CARD) family, and the caspase family. Here, we review the role of apoptosispathway protein groups in the CLL microenvironment and strategies to countersurvival signals of these groups as approaches in CLL therapy.Keywords Apoptosis pathways • Chronic lymphocytic leukemia • Microenviron-ment factors • Therapeutic strategies • B-cell receptor • Bcl-2 family • TNF receptorsuper familyV. Patel • K. BalakrishnanDepartments of Experimental Therapeutics, The University of Texas M.D. Anderson CancerCenter, P.O. Box 301429, Houston, TX, USAV. Gandhi (*)Departments of Experimental Therapeutics, The University of Texas M.D. Anderson CancerCenter, P.O. Box 301429, Houston, TX, USADepartments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston,TX, USAe-mail: vgandhi@mdanderson.org© Springer International Publishing Switzerland 2015V. Gandhi et al. (eds.), Multi-Targeted Approach to Treatment of Cancer,DOI 10.1007/978-3-319-12253-3_473