Highlights of This Issue

Abstract

Acute myeloid leukemia (AML) is generally amenable to first-line chemotherapeutics that typically induce a remission. However, at least 40% of AML patients will experience a relapse, suggesting that AML cells either acquire resistance or originate from a stem cell population. Leukemia-initiating cells (LIC) are believed to be important for AML growth and are thought to be responsible for AML relapses. Therefore, strategies specifically targeting LICs are of translational interest. Weidenaar and colleagues evaluated a receptor tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK), using long-term cocultures of pediatric CD34+ AML cells. Critically, PTK/ZK inhibited outgrowth and self-renewal of LICs when cultured up to 10 weeks. Proteome profiler kinase array analysis of downstream signaling systems revealed that PTK/ZK reduced activation of phosphoinositide 3-kinase/Akt kinase signaling. Treatment of AML cells with an Akt inhibitor showed similar results, whereas antibodies against VEGFA and VEGF receptors did not. These data suggest that targeting of multiple kinase pathways with PTK/ZK could be a promising approach to improve AML outcomes.The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is upregulated in many cancer types and is considered a putative therapeutic target. Garipov and colleagues report that EZH2 is upregulated in ovarian cell lines and in expression data from patients with ovarian cancer. They observed that transcriptional activation of EZH2 was dependent on 2 NF-Y binding sites in the proximal region of the EZH2 promoter. Moreover, elevated expression of NF-YA, the regulatory subunit of NF-Y, was correlated with increased EZH2 expression and EZH2 was predictive of shorter patient survival. Mechanistically, depletion of NF-YA was sufficient to decrease EZH2 levels, which phenocopy EZH2 inhibition and result in apoptosis of cancer cells. This study establishes NF-Y as a key regulator of EZH2 expression and implies that targeting NF-Y represents an alternative strategy to inhibiting EZH2 activity in cancer.The origin recognition complex (ORC), composed of multiple DNA binding proteins that associate with origins of replication, is highly regulated throughout the cell cycle to avoid re-replication and potential genomic instability. In tumorderived cells, these ORC proteins are often expressed at high levels to accommodate the stress of replication. During replication, only a fraction of origins are used, while others are thought to remain dormant, and these “dormant” replication origins have been shown to enhance recovery from replication stress. Zimmerman and colleagues show that depletion of ORC1, ORC6, or CDC6 to levels that do not affect viability, which was considered optimal for the depletion of dormant origins without affecting normal replication, hypersensitized tumor-derived cells, but not immortalized, nontransformed cells, to replication stress. Additional study revealed that altering p53 or MYC affected the sensitivity of immortalized, nontransformed cells. These findings suggest that tumor cells have a greater reliance on origin licensing capacity, revealing ORC proteins as potential targets for therapeutic intervention.Prostate cancer is a leading cause of cancer associated death in men, due largely to disseminated disease. Unfortunately, the mechanisms that promote prostate cancer metastasis are not well studied, nor does an effective treatment exist for disseminated disease. To this end, the current study focused on the expression and role of the adhesion protein, β1 integrin. Lee and colleagues determined that β1 integrin and downstream phospho-FAK were increased in both primary prostate cancer and lymph node metastases. Moreover, highly metastatic prostate cancer cells were found to have higher constitutively active β1 integrin that correlated with resistance to anoikis. Antibody blockade of β1 integrin resulted in inhibition of phenotypes, signaling, and survival processes associated with metastatic potential. Finally, systemic delivery of a neutralizing antibody to β1 integrin suppressed metastasis to lymph nodes and to bone following orthotopic and intracardiac injections, respectively. Thus, constitutively active β1 integrin is a critical effector of prostate cancer metastasis, and these preclinical findings identify a potential target for metastasis prevention.