Strategies for induction of apoptosis by small molecules targeting p53 in hematological malignancies. (A) Nutlin-induced apoptosis in cells harboring wild type p53 can be mediated by p53-transcription-dependent and/or -independent pathways. In mutant p53 cell types, nutlin-induced apoptosis can be mediated by activation of p53 and/or p73. Small molecule RITA activates wild type p53 for the induction of apoptosis in different types of hematological malignancies including AML, CLL, and MM. However, in MM, RITA-induced activation of p53 can be mediated by either direct activation of p53 or through activation of the JNK signaling pathway. (B) PRIMA-1Met-induced apoptosis in AML and CLL cells has been shown to be p53 mutation status dependent. However, it can induce apoptosis in MM cells irrespective of p53 status or even in the absence of p53. The apoptosis induction by PRIMA-1Met in MM cells in the presence or absence of p53 as suggested by us is mediated by activation of p73 signaling. Small molecule MIRA-1, which has originally been described as a mutant p53 activator is shown to induce apoptosis of MM cells independent of p53 mutation status, i.e., it can induce apoptosis in MM cells harboring either wild type or mutant p53.