Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.

Malignant cells have a higher nicotinamide adenine dinucleotide (NAD ؉) IntroductionMultiple myeloma (MM) is a clonal B-cell malignancy characterized by excessive bone marrow plasma cells in association with monoclonal protein. 1 The therapeutics currently available improve patients' survival and quality of life, but resistance to therapy and disease progression remain unsolved issues. Therefore, the definition of new aspects of MM biology that can be targeted and exploited from a therapeutic perspective remains a major basic and clinical research goal.Autophagy is a conserved process of normal cell turnover by regulating degradation of its components, which is characterized by the formation of autophagosomes, double-membrane cytoplasmic vesicles engulfing intracellular material including protein, lipids, as well as organelles, such as mitochondria and endoplasmic reticulum. Subsequently autophagosomes fuse with lysosomes, and their contents are degradated by lysosomal enzymes. 2 This selfcannibalization event is a highly conserved response to metabolic stress, in which cellular components are degraded for the maintenance of homeostasis. 3 Intriguingly, the waste removal function of autophagy appears as to be a double-edged sword, because it can either lead to cell survival or death. 4 A series of molecular mechanisms coordinate the autophagy machinery. Specifically, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is the major intracellular hub for integrating autophagy-related signals. 5 Upstream of mTORC1 is the cellular energy-sensing pathway. 6 Regulation of autophagy also occurs through the transcription factors EB (TFEB) and forkhead box (FOXO), whose activation leads to transcription of Atg genes. 7,8 Although apoptosis induction has been the major focus of research in novel MM therapies, a recent study documented a pivotal role for autophagy as a prosurvival mechanism in MM cells, suggesting its potential as an additional target for novel therapeutics. 9,10 Intracellular nicotinamide adenine nucleotide (NAD ϩ ) plays a major role in the regulation of several cellular processes. 11,12 In mammals, NAD ϩ is replenished from nicotinamide (Nam), tryptophan or nicotinic acid (NA), with Nam as the most important and widely available precursor. 13 Nicotinamide phosphoribosyltransferase (NAMPT), pre-B colony enhancing factor, is the ratelimiting enzyme in NAD ϩ synthesis from Nam. 14 The expression of this enzyme is up-regulated in activated immune cells, 15 in differentiated myeloid cells, 16 during the circadian clock, 17 in glucose-restriction impaired skeletal myoblast differentiation, 18 and during cytokine production in immune cells. 19 Importantly, Nampt is also overexpressed in cancer cells, which exhibit a significant dependence on NAD ϩ to support their rapid cell proliferation. 20 Importantly, a specific chemical inhibitor of Nampt FK866, also called APO866 or WK175, exhibits a broad antitumor activity both in vitro and in vivo against cell lines derived from several tumors, with a favorabl...

No abstract