Hot off the presses! Jul 12 Cancer Cell

The Jul 12 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:

• The Role of TET2 in Hematologic Neoplasms
  - Cancer Cell 20(1):1-2 (2011)
  TET2 encodes an enzyme that hydroxylates methylcytosine and is frequently targeted by loss-of-function mutations in myelodysplasia, myeloproliferative disorders, and acute myeloid leukemia. In this issue of Cancer Cell, two studies show that inactivation of Tet2 enhances hematopoietic stem cell self renewal and promotes the development of myeloproliferative disorders.
• BCL6: A Novel Target for Therapy of Ph+ B Cell Acute Lymphoblastic Leukemia
  - Cancer Cell 20(1):3-5 (2011)
  BCL6 is a zinc-finger transcriptional repressor known for its oncogenic role in B cell lymphoma. In a recent issue of Nature, Duy et al. describe a novel role for BCL6 at the center of a transcriptional network in Ph+ acute lymphoblastic leukemia cells that modulates their leukemogenicity and response to kinase inhibitors.
• Comprehensive Identification of Somatic Mutations in Chronic Lymphocytic Leukemia
  - Cancer Cell 20(1):5-7 (2011)
  Massively parallel sequencing enables the sequencing of whole genomes, exomes, and transcriptomes from many tumor samples. Thus, it now is possible to comprehensively identify somatic mutations, including single base changes, deletions, insertions, and genomic rearrangements. Early results for hematopoietic tumors show great promise, but many questions remain to be answered.
• Beefing up Prostate Cancer Therapy with Performance-Enhancing (Anti-) Steroids
  - Cancer Cell 20(1):7-9 (2011)
  In the May 26th issue of the New England Journal of Medicine, de Bono et al. report that the inhibition of androgen synthesis by abiraterone acetate prolonged the survival of men with prostate cancer previously treated by androgen suppression.
• Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid Transformation
  - Cancer Cell 20(1):11-24 (2011)
  Somatic loss-of-function mutations in the ten-eleven translocation 2 (TET2) gene occur in a significant proportion of patients with myeloid malignancies. Although there are extensive genetic data implicating TET2 mutations in myeloid transformation, the consequences of Tet2 loss in hematopoietic development have not been delineated. We report here an animal model of conditional Tet2 loss in the hematopoietic compartment that leads to increased stem cell self-renewal in vivo as assessed by competitive transplant assays. Tet2 loss leads to a progressive enlargement of the hematopoietic stem cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis, and extramedullary hematopoiesis. In addition, Tet2+/− mice also displayed increased stem cell self-renewal and extramedullary hematopoiesis, suggesting that Tet2 haploinsufficiency contributes to hematopoietic transformation in vivo.
• TET2 Inactivation Results in Pleiotropic Hematopoietic Abnormalities in Mouse and Is a Recurrent Event during Human Lymphomagenesis
  - Cancer Cell 20(1):25-38 (2011)
  Loss-of-function mutations affecting one or both copies of the Ten-Eleven-translocation (TET)2 gene have been described in various human myeloid malignancies. We report that inactivation of Tet2 in mouse perturbs both early and late steps of hematopoiesis including myeloid and lymphoid differentiation in a cell-autonomous manner, endows the cells with competitive advantage, and eventually leads to the development of malignancies. We subsequently observed TET2 mutations in human lymphoid disorders. TET2 mutations could be detected in immature progenitors endowed with myeloid colony-forming potential. Our results show that the mutations present in lymphoid tumor cells may occur at both early and later steps of lymphoid development and indicate that impairment of TET2 function or/and expression predisposes to the development of hematological malignancies.
• Cell of Origin in AML: Susceptibility to MN1-Induced Transformation Is Regulated by the MEIS1/AbdB-like HOX Protein Complex
  - Cancer Cell 20(1):39-52 (2011)
  Pathways defining susceptibility of normal cells to oncogenic transformation may be valuable therapeutic targets. We characterized the cell of origin and its critical pathways in MN1-induced leukemias. Common myeloid (CMP) but not granulocyte-macrophage progenitors (GMP) could be transformed by MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that MN1-leukemogenicity required the MEIS1/AbdB-like HOX-protein complex. ChIP-sequencing identified common target genes of MN1 and MEIS1 and demonstrated identical binding sites for a large proportion of their chromatin targets. Transcriptional repression of MEIS1 targets in established MN1 leukemias demonstrated antileukemic activity. As MN1 relies on but cannot activate expression of MEIS1/AbdB-like HOX proteins, transcriptional activity of these genes determines cellular susceptibility to MN1-induced transformation and may represent a promising therapeutic target.
• Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor
  - Cancer Cell 20(1):53-65 (2011)
  Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.
• MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
  - Cancer Cell 20(1):66-78 (2011)
  The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.
• A Pin1/Mutant p53 Axis Promotes Aggressiveness in Breast Cancer
  - Cancer Cell 20(1):79-91 (2011)
  TP53 missense mutations dramatically influence tumor progression, however, their mechanism of action is still poorly understood. Here we demonstrate the fundamental role of the prolyl isomerase Pin1 in mutant p53 oncogenic functions. Pin1 enhances tumorigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent transformation. In breast cancer cells, Pin1 promotes mutant p53 dependent inhibition of the antimetastatic factor p63 and induction of a mutant p53 transcriptional program to increase aggressiveness. Furthermore, we identified a transcriptional signature associated with poor prognosis in breast cancer and, in a cohort of patients, Pin1 overexpression influenced the prognostic value of p53 mutation. These results define a Pin1/mutant p53 axis that conveys oncogenic signals to promote aggressiveness in human cancers.
• Proinvasion Metastasis Drivers in Early-Stage Melanoma Are Oncogenes
  - Cancer Cell 20(1):92-103 (2011)
  Clinical and genomic evidence suggests that the metastatic potential of a primary tumor may be dictated by prometastatic events that have additional oncogenic capability. To test this "deterministic" hypothesis, we adopted a comparative oncogenomics-guided function-based strategy involving: (1) comparison of global transcriptomes of two genetically engineered mouse models with contrasting metastatic potential, (2) genomic and transcriptomic profiles of human melanoma, (3) functional genetic screen for enhancers of cell invasion, and (4) evidence of expression selection in human melanoma tissues. This integrated effort identified six genes that are potently proinvasive and oncogenic. Furthermore, we show that one such gene, ACP5, confers spontaneous metastasis in vivo, engages a key pathway governing metastasis, and is prognostic in human primary melanomas.
• miR-30b/30d Regulation of GalNAc Transferases Enhances Invasion and Immunosuppression during Metastasis
  - Cancer Cell 20(1):104-118 (2011)
  To metastasize, a tumor cell must acquire abilities such as the capacity to colonize new tissue and evade immune surveillance. Recent evidence suggests that microRNAs can promote the evolution of malignant behaviors by regulating multiple targets. We performed a microRNA analysis of human melanoma, a highly invasive cancer, and found that miR-30b/30d upregulation correlates with stage, metastatic potential, shorter time to recurrence, and reduced overall survival. Ectopic expression of miR-30b/30d promoted the metastatic behavior of melanoma cells by directly targeting the GalNAc transferase GALNT7, resulted in increased synthesis of the immunosuppressive cytokine IL-10, and reduced immune cell activation and recruitment. These data support a key role of miR-30b/30d and GalNAc transferases in metastasis, by simultaneously promoting cellular invasion and immunosuppression.
• Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer
  - Cancer Cell 20(1):119-131 (2011)
  Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25%–30% of cases that are ER negative (ER–). Androgen receptor (AR) is expressed in 60%–70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER– breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER–/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER–/HER2+ breast cancers.
• Turning Reciprocal Feedback Regulation into Combination Therapy
  - Cancer Cell 20(1):132 (2011)