Hot off the presses! Oct 19 Cancer Cell

The Oct 19 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• MicroRNA Biogenesis Takes Another Single Hit from Microsatellite Instability
  - Cancer Cells 18(4):295-297 (2010)
  In this issue of Cancer Cell, Melo et al. show that mutation of a single allele of the Exportin-5 gene (XPO5) suffices to depress microRNA (miRNA) levels and promote tumorigenesis. Thus, XPO5 joins the ranks of DICER and TRBP as a haploinsufficient tumor suppressor in the miRNA biogenesis pathway.
• T-Lineage Lymphoblastic Lymphoma and Leukemia—a MASSive Problem
  - Cancer Cells 18(4):297-299 (2010)
  T cell precursor malignancies may present as T-lymphoblastic lymphoma (T-LBL) with marked enlargement of lymph nodes or acute T-lymphoblastic leukemia (T-ALL) with little lymph node enlargement. In this issue of Cancer Cell, Feng et al. show that dysregulation of BCL2, AKT signaling, and cell adhesion pathways are hallmarks of T-LBL.
• Epigenetics and MicroRNAs Combine to Modulate the MDM2/p53 Axis in Myeloma
  - Cancer Cells 18(4):299-300 (2010)
  Avoiding the inhibitory effects of p53 on cell growth is important for tumor progression. In this issue of Cancer Cell, Picchiorri et al. describe epigenetic silencing of MDM2-targeting microRNAs in multiple myeloma (MM), which generally appears to have intact p53 function. This provides the rationale for microRNA-targeted therapy for MM.
• BRAF Inhibitor Unveils Its Potential against Advanced Melanoma
  - Cancer Cells 18(4):301-302 (2010)
  Unresponsiveness to therapy is a hallmark feature of advanced metastatic melanoma. However, the discovery of BRAF-activating mutations in approximately 50% of human melanomas has provided an attractive therapeutic target. Here, we discuss two recent publications focusing on the mutant BRAF kinase inhibitor PLX4032 that validate oncogene-targeted melanoma therapy.
• A Genetic Defect in Exportin-5 Traps Precursor MicroRNAs in the Nucleus of Cancer Cells
  - Cancer Cells 18(4):303-315 (2010)
  The global impairment of mature microRNAs (miRNAs) is emerging as a common feature of human tumors. One interesting scenario is that defects in the nuclear export of precursor miRNAs (pre-miRNAs) might occur in transformed cells. Exportin 5 (XPO5) mediates pre-miRNA nuclear export and herein we demonstrate the presence of XPO5-inactivating mutations in a subset of human tumors with microsatellite instability. The XPO5 genetic defect traps pre-miRNAs in the nucleus, reduces miRNA processing, and diminishes miRNA-target inhibition. The XPO5 mutant form lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and pre-miRNAs accumulate in the nucleus. Most importantly, the restoration of XPO5 functions reverses the impaired export of pre-miRNAs and has tumor-suppressor features.
• Epigenetic Antagonism between Polycomb and SWI/SNF Complexes during Oncogenic Transformation
  - Cancer Cells 18(4):316-328 (2010)
  Epigenetic alterations have been increasingly implicated in oncogenesis. Analysis of Drosophila mutants suggests that Polycomb and SWI/SNF complexes can serve antagonistic developmental roles. However, the relevance of this relationship to human disease is unclear. Here, we have investigated functional relationships between these epigenetic regulators in oncogenic transformation. Mechanistically, we show that loss of the SNF5 tumor suppressor leads to elevated expression of the Polycomb gene EZH2 and that Polycomb targets are broadly H3K27-trimethylated and repressed in SNF5-deficient fibroblasts and cancers. Further, we show antagonism between SNF5 and EZH2 in the regulation of stem cell-associated programs and that Snf5 loss activates those programs. Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss.
• Nuclear Cyclin D1/CDK4 Kinase Regulates CUL4 Expression and Triggers Neoplastic Growth via Activation of the PRMT5 Methyltransferase
  - Cancer Cells 18(4):329-340 (2010)
  Cyclin D1 elicits transcriptional effects through inactivation of the retinoblastoma protein and direct association with transcriptional regulators. The current work reveals a molecular relationship between cyclin D1/CDK4 kinase and protein arginine methyltransferase 5 (PRMT5), an enzyme associated with histone methylation and transcriptional repression. Primary tumors of a mouse lymphoma model exhibit increased PRMT5 methyltransferase activity and histone arginine methylation. Analyses demonstrate that MEP50, a PRMT5 coregulatory factor, is a CDK4 substrate, and phosphorylation increases PRMT5/MEP50 activity. Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth, including CUL4 repression, CDT1 overexpression, and DNA rereplication. Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity.
• Myeloid Leukemia Development in c-Cbl RING Finger Mutant Mice Is Dependent on FLT3 Signaling
  - Cancer Cells 18(4):341-352 (2010)
  Although myeloid leukemias are primarily caused by leukemic stem cells, the molecular basis of their transformation remains largely unknown. Here, by analyzing mice with a mutation in the RING finger domain of c-Cbl, we show that the E3 ubiquitin ligase activity of c-Cbl is required to restrict myeloid leukemia development. These mice develop a myeloproliferative disease which progresses to leukemia and involves hematopoietic progenitors that exhibit augmented FLT3 signaling. Suppressing this signaling through matings with FLT3 ligand knockout mice prevents leukemia development. We also observe enhanced c-Kit, Akt and Erk activity, and deregulated expression of leukemia-associated transcription factors in hematopoietic progenitors. The characterization of these perturbations provides direction for therapeutics that may aid the treatment of patients with c-Cbl mutations.
• T-Lymphoblastic Lymphoma Cells Express High Levels of BCL2, S1P1, and ICAM1, Leading to a Blockade of Tumor Cell Intravasation
  - Cancer Cells 18(4):353-366 (2010)
  The molecular events underlying the progression of T-lymphoblastic lymphoma (T-LBL) to acute T-lymphoblastic leukemia (T-ALL) remain elusive. In our zebrafish model, concomitant overexpression of bcl-2 with Myc accelerated T-LBL onset while inhibiting progression to T-ALL. The T-LBL cells failed to invade the vasculature and showed evidence of increased homotypic cell-cell adhesion and autophagy. Further analysis using clinical biopsy specimens revealed autophagy and increased levels of BCL2, S1P1, and ICAM1 in human T-LBL compared with T-ALL. Inhibition of S1P1 signaling in T-LBL cells led to decreased homotypic adhesion in vitro and increased tumor cell intravasation in vivo. Thus, blockade of intravasation and hematologic dissemination in T-LBL is due to elevated S1P1 signaling, increased expression of ICAM1, and augmented homotypic cell-cell adhesion.
• Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development
  - Cancer Cells 18(4):367-381 (2010)
  In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development.
• Pharmacologic Inhibition of the Anaphase-Promoting Complex Induces A Spindle Checkpoint-Dependent Mitotic Arrest in the Absence of Spindle Damage
  - Cancer Cells 18(4):382-395 (2010)
  Microtubule inhibitors are important cancer drugs that induce mitotic arrest by activating the spindle assembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the anaphase-promoting complex (APC). Here, we report a small molecule, tosyl-L-arginine methyl ester (TAME), which binds to the APC and prevents its activation by Cdc20 and Cdh1. A prodrug of TAME arrests cells in metaphase without perturbing the spindle, but nonetheless the arrest is dependent on the SAC. Metaphase arrest induced by a proteasome inhibitor is also SAC dependent, suggesting that APC-dependent proteolysis is required to inactivate the SAC. We propose that mutual antagonism between the APC and the SAC yields a positive feedback loop that amplifies the ability of TAME to induce mitotic arrest.
• Pharmacological Inhibition of BMK1 Suppresses Tumor Growth through Promyelocytic Leukemia Protein
  - Cancer Cells 18(4):396 (2010)
  
• Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation
  - Cancer Cells 18(4):397 (2010)