Prosurvival signaling pathways and their downstream targets. This is a schematic illustration of the principal pathways that are discussed in this paper. Growth factors induce, or membrane-associated molecules dimerize, spontaneously to activate mitogen-activated protein kinases (Raf/MEK/ERK) and PI3K/AKT signaling pathways. Transmembrane G protein–coupled receptors can activate PKC, which modulates the activity of Raf and MAPK pathway; both ERK1/2 and PKCα can serve as Bcl-2 kinases at serine 70. AKT and ERK induce phosphorylation of Bim (AKT, at serine 87 and ERK, at serines 55, 65, and 100), which attenuates the proapoptotic function of Bim, thereby promoting cell survival. Phosphorylation of Bad by MAPK (serine 112) or AKT (serine 136) inhibits apoptosis due to loss of the ability of Bad to heterodimerize with the survival proteins Bcl-2 and Bcl-X_L. Hence, prosurvival phosphorylation of Bcl-2 family proteins modulates their antiapoptotic or proapoptotic activity at the mitochondrial membrane. This is complemented by AKT- or MAPK-driven gene transcription, which includes cyclins D and E (MAPK), cyclin-dependent kinase inhibitor p21, c-myc (AKT), which cause an increase in cell proliferation; and antiapoptotic proteins of the Bcl-2 (Mcl-1) and IAP (XIAP, survivin) families that regulate apoptosis at the level (Mcl-1) or downstream of mitochondria (IAPs). It is apparent that simultaneous activation of multiple signaling pathways might synergistically enhance prosurvival and proliferative potential of leukemic cells and the redundant downstream pathways negatively affect an ability of a particular signal transduction inhibitor to eliminate leukemia.