2011

Comprehensive genomic DNA analysis of mast cell leukemia uncovers clues that could improve therapy
Research Investigator Mona Spector, working with Ivan Iossifov, Scott Lowe and collaborators at North Shore University Hospital-Long Island Jewish Medical Center identified two previously unknown mutations from a patient with mast cell leukemia (MCL), an extremely aggressive subtype of acute myeloid leukemia (AML) with a very poor prognosis. The identification of these mutations suggests new possibilities for alternative screening and treatments for MCL.  Spector et al. (2011) Leukemia Dec 16 [Epub ahead of print].
PubMed | Press Release

Novel regulatory role of hydrogen sulfide in cell response to protein misfolding
Small amounts of H₂S are produced when the cell is under ER stress, and Nicholas Tonks and Darryl Pappin discovered that H₂S covalently modifies the active-site cysteine residue of protein tyrosine phosphatase 1B (PTP1B), inactivating the enzyme.  Inactivation of PTP1B prevents dephosphorylation of PERK.  Active PERK can then phosphorylate the eukaryotic translational initiation factor 2, thereby attenuating protein translation and reducing ER stress. The process is fully reversible, thus the inactivation and reactivation of PTP1B is a novel mechanism by which the cell can regulate its protein synthesis machinery. Krishnan et al. (2011) Sci Signal 4(203):ra86.
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Structure of RITS complex explains its role in heterochromatin assembly and gene silencing
Leemor Joshua-Tor and colleagues used x-ray crystallography to determine how the three components of the RNA-Induced Initiation of Transcriptional gene Silencing (RITS) interact with each other, revealing new details in the interaction between Chp1 and Tas3, and identifying a new Chp1 domain associated with telomeres.  Schalch  et al.  (2011) Nat Struct Mol Biol. 18(12):1351-7.
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Study reveals details of alternative splicing circuitry that promote cancer’s Warburg effect
Adrian Krainer and colleagues from Harvard Medical School showed that the splicing factor SRSF3 is a key determinant in regulating which isoform of pyruvate kinase is expressed in cancer cells. Their findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect, and also have implications for other genes with a similar pattern of alternative splicing.  Wang et al. (2011) J Mol Cell Biol. Nov 1 [Epub ahead of print].
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New role for RNAi during chromosomal replication 
Rob Martienssen’s team used S. pombe to study how the transcription machinery and replication machinery are coordinated during the replication stage of the cell cycle, demonstrating that an RNAi mediated mechanism removes RNA pol II from replicating DNA to allow the replication fork to progress.  Zaratiegui et al. (2011) Nature 479(7371):135-8.
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Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activation
Using live cell imaging, David Spector’s group demonstrated that genes “bookmarked” by an acetylated histone (H4K5Ac) during interphase leads to accelerated transcriptional activation after mitosis through recruitment of the bromodomain protein BRD4. Zhao et al. (2011) Nat Cell Biol. 13(11):1295-304.
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Discovery of a new prostate tumor suppressor gene
Lloyd Trotman and colleagues showed that PHLPP1, a phosphatase that inactivates AKT, is a prostate tumor suppressor.   Loss of PHLPP1 alone causes neoplasia, while simultaneous loss of PHLPP1 and PTEN is associated with metastatic disease.  These results identify PHLPP1 as one of several key players, along with p53, PTEN and PHLPP2, acting as a barrier against prostate cancer progression.  Chen et al. (2011) Cancer Cell 20(2):173-86.
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Discovery of potential treatment for AML 
Chris Vakoc and colleagues identified the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance in acute myloid leukemia (AML). Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukemic effects in vitro and in vivo. These results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML.  Zuber et al.  (2011) Nature 478(7370):524-8.
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2010

Discovery of new mechanisms related to therapy-resistance in lung cancer
A team led by Raffaella Sordella identified new ways in which non-small cell lung cancer cells develop resistance to Tarceva (erlotinib), a small-molecule drug that targets EGFR signaling. Their discovery that increased IL-6 secretion decreases tumor cell sensitivity to Tarceva suggests a new way of overcoming resistance. Yao et al. (2010) PNAS 107(35):15535-40.
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p53 loss promotes acute myeloid leukemia
Scott Lowe’s lab discovered that mutations in two genes, p53 and Kras, reinforce one another, causing precursor blood cells to proliferate out of control. Zuber et al. (2010) Genes and Development 24(13):1389-402.
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Alternative pathway for generating microRNAs is uncovered
Greg Hannon and colleagues discovered that one of the argonaute proteins, Ago2, is involved in an alternative pathway of microRNA generation, explaining one of the evolutionary needs for retaining Ago2’s enzymatic activity in mammals. Cheloufi et al. (2010) Nature 465(7298):584-9.
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The tumor suppressor Retinoblastoma (RB) represses DNA replication genes during senescence
A team led by Scott Lowe found that RB’s tumor suppression activity is due to its ability to induce cellular senescence by selective targeting of genes involved with DNA replication. Chicas et al. (2010) Cancer Cell 17(4):313-4.
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Role of a protein critical for activating DNA replication uncovered
Bruce Stillman and colleagues discovered that DDK, an enzyme known to be essential for activating DNA replication, performs this role by phosphorylating Mcm4, which subsequently leads to the unwinding of DNA. Sheu and Stillman. (2010) Nature 463(7277):113-7.
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Study identifies potential way to reverse cancer cell metabolism and tumor growth
Adrian Krainer and colleagues identified factors that contribute to high levels of the cancer-related enzyme PK-M2 through the use of alternative splicing. Controlling the splicing process for this gene could provide a new therapeutic avenue to treat cancer. Clower et al. (2010) PNAS 107(5):1894-9.
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Study of breast tumor heterogeneity provides insights into tumor progression
A group led by Mike Wigler developed a method to study genomic heterogeneity in breast cancer tumors, allowing them to identify subpopulations within tumors as well as map their spatial organization; this analysis can be used to advance our understanding of the genetic pathways of tumor progression. Navin et al. (2010) Genome Research 20(1):68-80.
PubMed

 

2009

Protein identified as a marker designating highly active genes following cell division
CSHL Fellow Chris Vakoc discovered that the protein Mixed Lineage Leukemia (MLL) serves as a “bookmark” for passing on information from parent to daughter cell about which genes need to be activated after cell division. Blobel et al. (2009) Molecular Cell 36(6):970-83.
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Development of mouse model of leukemia that accurately predicts response to chemotherapy
Scott Lowe and colleagues developed new mouse models for human acute myeloid leukemia (AML) that precisely recapitulate genetic associations linked to treatment responses in human patients. The new models serve as an effective test system for new drugs and treatment strategies in AML. Zuber et al. (2009) Genes and Development 23(7):877-89.
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The tumor suppressor p63 TA isoforms trigger senescence and suppress tumor formation
The Alea Mills lab discovered that TAp63 isoforms are active tumor suppressors that regulate senescence through p53-independent pathways, thus pointing to a way to treat p53-deficient tumors. Guo et al. (2009) Nat Cell Biol 11(12):1451-7.
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Identification and characterization of a new class of small RNAs
As part of the multinational ENCODE project, CSHL scientists Tom Gingeras and Greg Hannon discovered a new class of small RNAs, and found evidence that some of these molecules could have a role in controlling gene expression. Affymetrix ENCODE Transcriptome Project (2009) Nature 457(7232):1028-32.
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Novel tumor suppressor identified in epithelial cancer
A multi-investigator effort involving the Hannon, Muthuswamy and Powers labs identified Cyfip1, a gene commonly deleted in human epithelial cancers, as a tumor suppressor that controls cell movement and suppresses tumor invasion. Silva et al. (2009) Cancer Cell 137(6):1047-61.
PubMed

Link between DNA replication and chromosome segregation
Bruce Stillman’s lab showed that subunits of the Origin recognition Complex (ORC) are involved in heterochromatin maintenance, centromere and kinetochore function, centrosome copy number and function and cytokinesis. This study, combined with earlier work, shows that key proteins required for DNA replication are linked to control of many aspects of chromosome segregation. Hemerly et al (2009). Science 323(5915):789-93.
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Identification of oncogenes & tumor suppressors [multiple years]
CSHL Cancer Center scientists used genomics methods to screen human cancer samples for genomic regions that are commonly deleted or amplified in cancer. An approach combining RNAi tools and innovative animal models was used to identify cancer-associated genes in a variety of cancer types:

• Zender  et al (2008).  Tumor suppressors in liver cancer.  Cell 135(5):852-64  PubMed
• Bric et al  (2009).  Tumor suppressors in mouse lymphoma model. Cancer Cell. 16(4):324-35  PubMed
• Zender et al (2006) Oncogenes in liver cancer. Cell 125:1253-67  PubMed
• Kendall et al (2007) Oncogenes in lung cancer. Proc Natl Acad Sci U S A. 104:16663-8  PubMed
• Xue et al, (2008). Tumor suppressor in hepatocellular carcinoma.  Genes and Development 22(13):1724-30  PubMed

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2008

Proteins that control cell shape are a new class of molecules that regulate cancer
Senthil Muthuswamy and colleagues demonstrated that normal function of a protein called Scribble allows breast epithelial cells to form duct-like structures and resist cancer formation. This could lead to new anti-cancer therapies targeting this class of molecules and pathways involved in cellular architecture. Zhan et al. (2008) Cell 135(5):865-78
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Demonstration of a role for NADP in induction of gene regulation in a metabolic pathway
Leemor Joshua-Tor and colleagues uncovered a previously unknown role for nicotinamide adenine dinucleotide phosphate (NADP) in metabolism, showing that it induces a transcriptional regulatory network that switches on the genes necessary for metabolizing galactose. Their discovery suggests that targeting these regulatory genes might offset the aberrant metabolism seen in cancer. Kumar PR, et al. Science. 2008 Feb 22;319(5866):1090-2.
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New mechanism for inheritance of epigenetic information identified
A study from Greg Hannon’s lab demonstrated an epigenetic role for maternally inherited piRNAs in transposon silencing. Brennecke et al. (2008) Science 322(5906):1387-92.
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2007

Non coding microRNA can act as oncogene or tumor suppressor
Greg Hannon and Scott Lowe observed that microRNAs can act as tumor suppressors and identified miR34 as a component of the p53 network. He et al. (2007) Nature 447(7148):1130-4.
PubMed

Discovery of CHD5 tumor suppressor
Alea Mills identified a new tumor suppressor gene CHD5, located on human chromosome 1p36, a region frequently deleted in human cancers. The gene appears to be a master control gene that regulates the p53 pathway. Bagchi, et al. (2007). Cell 128(3):459-75.
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Splicing factor SF2/ASF is an oncogene
Adrian Krainer found that splicing factor SF2/ASF - one of the proteins involved in determining which alternative splice product is produced - is itself a proto-oncogene, suggesting that imbalances in RNA splicing can contribute to human cancer. This could provide new therapeutic strategies for treatment of the disease. Karni, et al. (2007). Nat Struct Mol Biol 14(3):185-93.
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Reactivating p53 tumor suppressor causes tumors to regress
Scott Lowe showed that even brief reactivation of the p53 tumor suppressor gene in p53-deficient tumors can produce complete tumor regression and triggers an innate immune response that targets tumor cells in vivo and contributes to tumor clearance. Xue, et al. (2007). Nature 445(7128):656-60.
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2006

Innovative strategy used to identify new tumor-associated genes in liver cancer
Scott Lowe, Scott Powers and others identified two genes overexpressed in hepatocellular carcinoma - cIAP and YAP. This study, which involved five research groups at CSHL in addition to collaborators in five other institutions in Europe, Asia, Australia, and the U.S, demonstrates that novel and accurate animal models, combined with comparison to human genomic data, can be used to rapidly identify and validate new cancer genes. Zender, et al. (2006). Cell 125(7):1253-67.
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Genomic ‘firestorms’’ underlie aggressive breast cancer progression
In collaboration with scientists in Norway, Sweden and New York, Mike Wigler’s lab obtained genomic profiles for over 200 breast tumor samples with documented clinical history. The tumor samples were divided into three distinct groups based on the pattern of genomic variation. As these patterns correlate with clinical outcome, they can be used for clinical diagnosis and therapy. Hicks, et al. (2006). Genome Res 16(12):1465-7.
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2005

microRNAs linked to human cancer
In a collaboration between Scott Powers, Scott Lowe, Greg Hannon and colleagues at MSKCC, investigators demonstrated that a microRNA cluster can modulate tumor formation, the first implication that non-coding RNA’s can act as oncogenes. He, et al. (2005) Nature 435 (7043) 828-833.
PubMed

Loss of the tumor suppressor p63 accelerates aging
Alea Mills showed that deficiency of the p63 protein, a tumor suppressor related to p53, shortens life span in a mice due to activation of cellular senescence. Keyes et al. (2005) Genes and Development 19(17):1986-99.
PubMed

New gene regulation mechanism discovered
David Spector’s lab reported a novel mechanism for regulation of gene expression through retention of an mRNA precursor in the nucleus. Under conditions where protein production is needed immediately, the RNA is clipped, transported and expressed rapidly. Prasanth, et al. (2005) Cell 123, 249-253.
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