Role of RNA-Binding Proteins in BCR/ABL Leukemogenesis

Summary

Principal Investigator: D Perrotti
Affiliation: The Ohio State University
Country: USA
Abstract: Shuttling hnRNPs control the fate of eukaryotic mRNAs throughout their journey from the active site of transcription to that of translation; thus, gain or loss of their function in hematopoietic cells might result in altered hematopoiesis and/or emergence of leukemia. In BCR/ABL-expressing cells, there is a marked increase in the levels of different RNA binding proteins including FUS, hnRNP A1, hnRNP E2 and hnRNP K, four shuttling hnRNPs involved in the regulation of mRNA biogenesis, processing, nuclear export, and translation. Ectopic expression and/or inhibition of the activity of FUS, hnRNP A1 and hnRNP E2 affects the proliferation, survival, and differentiation of normal and BCR/ABL-expressing cells, suggesting that enhanced expression/activity of certain RNA-binding proteins plays an important but as yet unrecognized role in BCR/ABL leukemogenesis. Thus, the objective of this proposal is: 1) To investigate the mechanisms regulating hnRNP E2 and hnRNP A1 expression/function in BCR/ABL-expressing cells. 2) To identify hnRNP A1 and hnRNP E2-associated mRNAs encoding proteins differentially expressed in CML-blast crisis and CML-chronic phase cells. 3) To determine the BCR/ABL-dependent mechanisms regulating the expression/function of hnRNP K and determine whether hnRNP K function(s) is(are) required for BCR/ABL-induced leukemogenesis.
Funding Period: 2003-08-15 - 2007-07-31
more information: NIH RePORT

Top Publications

  1. ncbi BCR/ABL, mRNA translation and apoptosis
    D Perrotti
    Cell Death Differ 12:534-40. 2005
  2. ncbi TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells
    Rossana Trotta
    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210, USA
    J Immunol 181:3784-92. 2008
  3. ncbi Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias
    Danilo Perrotti
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
    Cancer Metastasis Rev 27:159-68. 2008
  4. ncbi Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-kappaB-dependent DNA methyltransferase activity in acute myeloid leukemia
    Shujun Liu
    Division of Hematology Oncology, The Ohio State University, Columbus, OH 43210, USA
    Blood 111:2364-73. 2008
  5. ncbi Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis
    Anna M Eiring
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, USA
    Blood 111:816-28. 2008
  6. ncbi The PP2A inhibitor SET regulates natural killer cell IFN-gamma production
    Rossana Trotta
    Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
    J Exp Med 204:2397-405. 2007
  7. ncbi FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma
    Qing Liu
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA
    Blood 111:275-84. 2008
  8. ncbi FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia
    Paolo Neviani
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
    J Clin Invest 117:2408-21. 2007
  9. ncbi CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha
    Steffen Koschmieder
    Department of Medicine, Hematology and Oncology, University of Munster, Münster Germany
    Blood 110:3695-705. 2007
  10. ncbi NPM/ALK binds and phosphorylates the RNA/DNA-binding protein PSF in anaplastic large-cell lymphoma
    Annamaria Galietta
    Department of Clinical Medicine, University of Milano Bicocca, Monza, Italy
    Blood 110:2600-9. 2007

Scientific Experts

  • D Perrotti
  • Steffen Koschmieder
  • Rossana Trotta
  • Paolo Neviani
  • Ramasamy Santhanam
  • Michael A Caligiuri
  • Guido Marcucci
  • Ji Suk Chang
  • Mario Notari
  • Anna M Eiring
  • Shujun Liu
  • Denis C Roy
  • Annamaria Galietta
  • John C Byrd
  • Carlo Gambacorti-Passerini
  • Clara D Bloomfield
  • Bradley W Blaser
  • A K Samanta
  • Qing Liu
  • Ching-Shih Chen
  • Joshua J Oaks
  • Natarajan Muthusamy
  • Ching Shih Chen
  • Tamara Vukosavljevic
  • Bruno Calabretta
  • Clara Guerzoni
  • Young Jin Lee
  • Peter Paschka
  • X Sun
  • J Hood
  • S N Chakraborty
  • Y Wang
  • R B Arlinghaus
  • H Kantarjian
  • Robert A Baiocchi
  • Esther Lehmann
  • Lai Chu Wu
  • Pierluigi Porcu
  • Lai-Chu Wu
  • Zhongfa Liu
  • Mitsui Takeki
  • Ramiro Garzon
  • Rebecca B Klisovic
  • James T Dalton
  • William Blum
  • Amy Lehman
  • Yihui Ma
  • Stefano Volinia
  • Gustavo W Leone
  • Jianhua Yu
  • Lenguyen Huynh
  • Zhiliang Xie
  • David Jarjoura
  • Xiaobin Zhao
  • Jiuxia Pang
  • Frank Frissora
  • Kenneth K Chan
  • William Willis
  • Oriano Marin
  • Angela Bachi
  • Carmen J Tartari
  • Nicole M Verrills
  • Emanuela Colombo
  • Edward Briercheck
  • Philip W Tucker
  • Sara Redaelli
  • Jorge Cortes
  • Rocco G Piazza
  • Paola Stano
  • Karen Pulford
  • Brian J Druker
  • Ching Jung Huang
  • Holger Ruchatz
  • Arianna Donella-Deana
  • Miriam Puttini
  • Carlo Gambacorti Passerini
  • Rosalind H Gunby
  • Ching-Jung Huang
  • Antonello Villa
  • Mattia Ronchetti
  • Cristiana Carniti
  • Daniel G Tenen
  • James W Vardiman
  • Rick A Kittles
  • Scott C Kogan
  • Jonathan E Kolitz
  • Amy S Ruppert
  • Ji-Suk Chang
  • Richard A Larson
  • Giovanna Ferrari-Amorotti

Detail Information

Publications19

  1. ncbi BCR/ABL, mRNA translation and apoptosis
    D Perrotti
    Cell Death Differ 12:534-40. 2005
  2. ncbi TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells
    Rossana Trotta
    Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210, USA
    J Immunol 181:3784-92. 2008
    ..This effect was accentuated in cells overexpressing SMAD3. Collectively, our results indicate that TGF-beta inhibits CD16-mediated human NK cell IFN-gamma production and ADCC, and these effects are mediated via SMAD3...
  3. ncbi Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias
    Danilo Perrotti
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
    Cancer Metastasis Rev 27:159-68. 2008
    ..Herein, we review current knowledge of PP2A biology and function with particular emphasis on its tumor suppressor activity and possible therapeutic implications in cancer...
  4. ncbi Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-kappaB-dependent DNA methyltransferase activity in acute myeloid leukemia
    Shujun Liu
    Division of Hematology Oncology, The Ohio State University, Columbus, OH 43210, USA
    Blood 111:2364-73. 2008
    ..Our results unveil the Sp1/NF-kappaB pathway as a modulator of DNA methyltransferase activity in human cancer and identify bortezomib as a novel epigenetic-targeting drug...
  5. ncbi Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis
    Anna M Eiring
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, USA
    Blood 111:816-28. 2008
    ..Thus, the complexity of the mRNA/RBP network, together with the discovery of E2F3 as an hnRNP-A1-regulated factor, outlines the relevant role played by RBPs in posttranscriptional regulation of CML development and progression...
  6. ncbi The PP2A inhibitor SET regulates natural killer cell IFN-gamma production
    Rossana Trotta
    Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
    J Exp Med 204:2397-405. 2007
    ..Thus, SET expression is essential for suppressing PP2A phosphatase activity that would otherwise limit NK cell antitumoral and/or antiinflammatory functions by impairing NK cell production of IFN-gamma...
  7. ncbi FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma
    Qing Liu
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA
    Blood 111:275-84. 2008
    ..These results provide the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies, including CLL...
  8. ncbi FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia
    Paolo Neviani
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
    J Clin Invest 117:2408-21. 2007
    ..Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients...
  9. ncbi CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha
    Steffen Koschmieder
    Department of Medicine, Hematology and Oncology, University of Munster, Münster Germany
    Blood 110:3695-705. 2007
    ..Because AML is characterized by arrested differentiation, our data suggest the inclusion of CDDO in the therapy of AML characterized by dysfunctional CEBPA expression...
  10. ncbi NPM/ALK binds and phosphorylates the RNA/DNA-binding protein PSF in anaplastic large-cell lymphoma
    Annamaria Galietta
    Department of Clinical Medicine, University of Milano Bicocca, Monza, Italy
    Blood 110:2600-9. 2007
    ..These results identify PSF as a novel NPM/ALK-binding protein and substrate, and suggest that PSF function may be perturbed in NPM/ALK-transformed cells...
  11. ncbi High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation
    Ji Suk Chang
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 23240, USA
    Blood 110:994-1003. 2007
    ..Furthermore, these findings suggest the inclusion of clinically relevant MAPK inhibitors in the therapy of CML-BC...
  12. ncbi From mRNA metabolism to cancer therapy: chronic myelogenous leukemia shows the way
    Danilo Perrotti
    The Molecular Biology and Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43240, USA
    Clin Cancer Res 13:1638-42. 2007
    ....
  13. ncbi ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia
    D Perrotti
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
    Br J Cancer 95:775-81. 2006
    ..Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients...
  14. ncbi Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study
    Peter Paschka
    Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
    J Clin Oncol 24:3904-11. 2006
    ..We suggest that patients with core-binding factor AML should be screened for mutKIT at diagnosis for both prognostic and therapeutic purposes, given that activated KIT potentially can be targeted with novel tyrosine kinase inhibitors...
  15. ncbi CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but differ in their antileukemic activities
    Young Jin Lee
    Dept of Laboratory Medicine, Box 0134, 513 Parnassus Ave, San Francisco, CA 94143, USA
    Blood 108:2416-9. 2006
    ..We also show that forced expression of C/EBPalpha or C/EBPepsilon in combination with ATRA treatment has a synergistic effect on survival of leukemic mice compared with either therapy alone...
  16. ncbi Inducible activation of CEBPB, a gene negatively regulated by BCR/ABL, inhibits proliferation and promotes differentiation of BCR/ABL-expressing cells
    Clara Guerzoni
    Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, 233 South and 10th Street, Philadelphia, PA 19107, USA
    Blood 107:4080-9. 2006
    ....
  17. ncbi A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation
    Mario Notari
    Human Cancer Genetics Program, The Ohio State University Medical Center, Columbus, OH 43240, USA
    Blood 107:2507-16. 2006
    ..Thus, BCR/ABL-dependent enhancement of HNRPK translation-regulation is important for BCR/ABL leukemogenesis and, perhaps, it might contribute to blast crisis transformation...
  18. ncbi The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein
    Paolo Neviani
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA
    Cancer Cell 8:355-68. 2005
    ..Thus, functional inactivation of PP2A is essential for BCR/ABL leukemogenesis and, perhaps, required for blastic transformation...
  19. ncbi Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients
    A K Samanta
    Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
    Oncogene 28:1669-81. 2009
    ..These results indicate that Lyn is downstream of Jak2, and Jak2 maintains activated Lyn kinase in CML through the SET-PP2A-Shp1 pathway...