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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in childhood. Despite the high cure-rate, identifying new druggable molecular targets is still of great interest. In a cohort of BCP-ALL pediatric patients, irrespectively of the molecule/karyotype lesions found, we recently observed high expression of c-Myc and Che-1/AATF, which disappears at time of remission. Study of the molecular mechanisms involved in this co-expression revealed that Che-1 expression was crucial for induction of blast-cell proliferation driven by c-Myc. Furthermore, Che-1/AATF silencing in primary BCP-ALL cell lines improves responsiveness to chemotherapy. These data individuate Che-1 as a possible novel target in the treatment of BCP-ALL able to affect c-Myc-driven tumorigenicity. [ABSTRACT FROM AUTHOR]

Whether PD-L1 expression is associated with survival outcomes in gastric cancer (GC) is controversial. The inhibition of the PD-1/PD-L1 pathway is effective against genomically unstable tumors. Hypothesizing that also the clinical significance of PD-L1 might be dependent on the activation of molecular circuits ensuring genomic stability, we evaluated PD-L1 expression in tissue samples from 72 advanced GC patients treated with first-line chemotherapy. Samples were already characterized for DNA damage repair (DDR) component expression (pATM, pChk1, pWee1, γ-H2AX and pRPA2) along with mutations in DDR-linked genes (TP53 and ARID1A). Overall, PD-L1 expression was not associated with progression-free survival (PFS) and overall survival (OS), independently on whether we considered its expression in tumor cells (PD-L1-TCs) or in the immune infiltrate (PD-L1-TILs). In subgroup analysis, positive PD-L1-TC immunostaining was associated with better PFS in patients whose tumors did not carry DDR activation (multivariate Cox: HR 0.34, 95%CI: 0.15-0.76, p = 0.008). This subset (DDRoff) was characterized by negative pATM expression or the presence of ARID1A mutations. Conversely, the relationship between PD-L1-TC expression and PFS was lost in a molecular scenario denoting DDR activation (DDRon), as defined by concomitant pATM expression and ARID1A wild-type form. Surprisingly, while PD-L1-TC expression was associated with better OS in the DDRoff subset (multivariate Cox: HR 0.41, 95% CI: 0.17-0.96, p = 0.039), in the DDRon subgroup we observed an opposite impact on OS (multivariate Cox: HR 2.56, 95%CI: 1.06-6.16, p = 0.036). Thus, PD-L1-TC expression may impact survival outcomes in GC on the basis of the activation/inactivation of genome-safeguarding pathways. [ABSTRACT FROM AUTHOR]

Reflecting the pivotal role of mammalian target of rapamycin (mTOR) in the cell, a number of pathways, several of which exhibit changes in expression or activity in different cancers, tightly control its activation. We have recently demonstrated that antiapoptotic transcription factor (AATF) regulates mTOR in response to several kinds of stress. [ABSTRACT FROM AUTHOR]

The NAD+-dependent histone deacetylase hSirT1 regulates cell survival and stress responses by inhibiting p53-, NF-αB-, and E2F1-dependent transcription. Here we show that the hSirT1/PCAF interaction controls the E2F1/p73 apoptotic pathway. hSirT1 represses E2F1-dependent P1p73 promoter activity in untreated cells and inhibits its activation in response to DNA damage. hSirT1, PCAF, and E2F1 are corecruited in vivo on theP1p73 promoter. hSirT1 deacetylates PCAF in vitro and modulates PCAF acetylation in vivo. In cells exposed to apoptotic DNA damage, nuclear NAD+ levels decrease and inactivate hSirT1 without altering the hSirT1 interaction with PCAF and hSirT1 binding to the P1p73 promoter. The reactivation of hSirT1 by pyruvate that increases the [NAD+]/[NADH] ratio completely abolished the DNA damage-induced activation of TAp73 expression, thus linking the modulation of chromatin-bound hSirT1 deacetylase activity by the intracellular redox state with P1p73 promoter activity. The release of PCAF from hSirT1 repression favors the assembly of transcriptionally active PCAF/E2F1 complexes onto the P1p73 promoter and p53-independent apoptosis. Our results identify hSirT1 and PCAF as potential targets to modulate tumor cell survival and chemoresistance irrespective of p53 status. [ABSTRACT FROM AUTHOR]