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 Intronic miR-3151 within BAALC drives leukemogenesis by deregulating the TP53 pathway
    Ann Kathrin Eisfeld
    The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
    Sci Signal 7:ra36. 2014
  2. pmc Precancerous stem cells have the potential for both benign and malignant differentiation
    Li Chen
    Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, United States of America
    PLoS ONE 2:e293. 2007
  3. pmc Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis
    Sahar A Saddoughi
    Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
    EMBO Mol Med 5:105-21. 2013
  4. pmc Protein phosphatase 2A: a target for anticancer therapy
    Danilo Perrotti
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210 2207, USA
    Lancet Oncol 14:e229-38. 2013
  5. pmc miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR
    M Y Balkhi
    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, The Ohio State University, Columbus, OH 43210, USA
    Sci Signal 6:ra63. 2013
  6. pmc Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies
    Joshua J Oaks
    Human Cancer Genetics Program, Department of Molecular Virology Immunology and Medical Genetics
    Blood 122:1923-34. 2013
  7. pmc Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias
    Christopher J Walker
    Human Cancer Genetics Program, Department Molecular Virology Immunology and Medical Genetics
    Blood 122:3034-44. 2013
  8. pmc PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells
    Paolo Neviani
    J Clin Invest 123:4144-57. 2013
  9. pmc miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts
    Anna M Eiring
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
    Cell 140:652-65. 2010
  10. pmc Essential requirement for PP2A inhibition by the oncogenic receptor c-KIT suggests PP2A reactivation as a strategy to treat c-KIT+ cancers
    Kathryn G Roberts
    School of Biomedical Sciences, University of Newcastle, Callaghan, New South Wales, Australia
    Cancer Res 70:5438-47. 2010

Scientific Experts

  • D Perrotti
  • Rossana Trotta
  • RICHARD A contact VAN ETTEN
  • Steffen Koschmieder
  • Paolo Neviani
  • Ramasamy Santhanam
  • Guido Marcucci
  • Michael A Caligiuri
  • Joshua J Oaks
  • Anna M Eiring
  • Christopher J Walker
  • Ann Kathrin Eisfeld
  • Sahar A Saddoughi
  • Jason G Harb
  • Shujun Liu
  • Denis C Roy
  • Ramiro Garzon
  • Ji Suk Chang
  • Mario Notari
  • John C Byrd
  • Clara D Bloomfield
  • John M Goldman
  • Alistair Reid
  • Besim Ogretmen
  • Jane Apperley
  • Dragana Milojkovic
  • Peter Hokland
  • Carlo M Croce
  • Annamaria Galietta
  • Jorge Cortes
  • Ching Shih Chen
  • Carlo Gambacorti-Passerini
  • Bradley W Blaser
  • Justin J Ellis
  • Gregory Ferenchak
  • M Y Balkhi
  • Ralph B Arlinghaus
  • Jacek Bielawski
  • Robert Bittman
  • Denis Claude Roy
  • Sebastian Schwind
  • Ravi Bhatia
  • Claudia S Huettner
  • William E Carson
  • Rebecca B Klisovic
  • William Blum
  • Yihui Ma
  • Stefano Volinia
  • Mark A Gregory
  • Kathryn G Roberts
  • A K Samanta
  • Brian J Druker
  • Nicole M Verrills
  • Qing Liu
  • Natarajan Muthusamy
  • Li Chen
  • Tamara Vukosavljevic
  • Bruno Calabretta
  • Clara Guerzoni
  • Young Jin Lee
  • Peter Paschka
  • Benjamin Leffel
  • Albert de la Chapelle
  • Tiina M Järvinen
  • Ravi Patel
  • Kevin W Hoag
  • Joseph Markowitz
  • Xiaomeng Huang
  • Charles Keller
  • Kyosuke Nagata
  • Omar Abdel-Wahab
  • Janelle A Solt
  • Adrienne M Dorrance
  • Peter J Houghton
  • Carolyn A Paisie
  • Robert V Stahelin
  • Shanmugam P Selvam
  • Bin Zhang
  • Raquela J Thomas
  • Dawn S Chandler
  • Chaode Sun
  • Angen Liu
  • Yosef Landesman
  • Nash Y Gabrail
  • Can E Senkal
  • Mark T Ziolo
  • O Hans Iwenofu
  • Zdzislaw M Szulc
  • Katherine J Ladner
  • Sharon Shacham

Detail Information

Publications35

  1. ncbi Intronic miR-3151 within BAALC drives leukemogenesis by deregulating the TP53 pathway
    Ann Kathrin Eisfeld
    The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
    Sci Signal 7:ra36. 2014
    ..Thus, this oncogenic miR-3151 may also have a role in solid tumors. ..
  2. pmc Precancerous stem cells have the potential for both benign and malignant differentiation
    Li Chen
    Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, United States of America
    PLoS ONE 2:e293. 2007
    ..We anticipate pCSCs to be a novel target for the early detection, prevention, and therapy of cancers...
  3. pmc Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis
    Sahar A Saddoughi
    Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
    EMBO Mol Med 5:105-21. 2013
    ..Thus, these data suggest that targeting I2PP2A/SET by FTY720 suppresses lung tumour growth, at least in part, via PP2A activation and necroptosis mediated by the kinase domain of RIPK1...
  4. pmc Protein phosphatase 2A: a target for anticancer therapy
    Danilo Perrotti
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210 2207, USA
    Lancet Oncol 14:e229-38. 2013
    ..Here, we discuss PP2A as a druggable tumour suppressor in view of the possible introduction of PP2A-activating drugs into anticancer therapeutic protocols...
  5. pmc miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR
    M Y Balkhi
    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, The Ohio State University, Columbus, OH 43210, USA
    Sci Signal 6:ra63. 2013
    ..Together, the findings reveal a unique role of miR-29 and suggest that its absence may contribute to sarcoma tumorigenesis. ..
  6. pmc Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies
    Joshua J Oaks
    Human Cancer Genetics Program, Department of Molecular Virology Immunology and Medical Genetics
    Blood 122:1923-34. 2013
    ..Thus, PADs (eg, FTY720) represent suitable therapeutic alternatives for Jak2(V617F) MPNs. ..
  7. pmc Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias
    Christopher J Walker
    Human Cancer Genetics Program, Department Molecular Virology Immunology and Medical Genetics
    Blood 122:3034-44. 2013
    ..Because XPO1 is important for leukemic cell survival, KPT-330 may represent an alternative therapy for TKI-refractory Ph(+) leukemias. ..
  8. pmc PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells
    Paolo Neviani
    J Clin Invest 123:4144-57. 2013
    ..Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs...
  9. pmc miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts
    Anna M Eiring
    Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
    Cell 140:652-65. 2010
    ..Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins...
  10. pmc Essential requirement for PP2A inhibition by the oncogenic receptor c-KIT suggests PP2A reactivation as a strategy to treat c-KIT+ cancers
    Kathryn G Roberts
    School of Biomedical Sciences, University of Newcastle, Callaghan, New South Wales, Australia
    Cancer Res 70:5438-47. 2010
    ..Our findings show that PP2A inhibition is essential for c-KIT-mediated tumorigenesis, and that reactivating PP2A may offer an attractive strategy to treat drug-resistant c-KIT(+) cancers...
  11. pmc Chronic myeloid leukemia: mechanisms of blastic transformation
    Danilo Perrotti
    Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 41230, USA
    J Clin Invest 120:2254-64. 2010
    ..The latter responds poorly to treatment and is usually fatal. Here, we discuss what is known about the molecular mechanisms leading to blastic transformation of CML and propose some novel therapeutic approaches...
  12. pmc Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl
    Mark A Gregory
    Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA
    Cancer Cell 18:74-87. 2010
    ..Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl(+) leukemias...
  13. pmc The PP2A inhibitor SET regulates granzyme B expression in human natural killer cells
    Rossana Trotta
    Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, 460 West 12th Ave, Columbus, OH 43210, USA
    Blood 117:2378-84. 2011
    ..These data provide evidence that granzyme B gene expression and therefore human NK-cell cytotoxicity can be regulated by the PP2A-SET interplay...
  14. pmc The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issues
    Richard A Van Etten
    Division of Hematology Oncology, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    Haematologica 96:590-601. 2011
    ..Finally, the clinical role of the new JAK2- and BCR-ABL1-inhibitors is considered. Much further progress is likely in several of these areas soon...
  15. ncbi BCR-ABL1 kinase-dependent alteration of mRNA metabolism: potential alternatives for therapeutic intervention
    Danilo Perrotti
    Human Cancer Genetics Program, Depatment of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center and Center for RNA Biology, The Ohio State University, Columbus, OH 43210 2207, USA
    Leuk Lymphoma 52:30-44. 2011
    ....
  16. pmc 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...
  17. pmc 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...
  18. 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...
  19. 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...
  20. pmc 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...
  21. pmc 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
    ....
  22. pmc 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...
  23. 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
    ..To analyze the prognostic impact of mutated KIT (mutKIT) in core-binding factor acute myeloid leukemia (AML) with inv(16)(p13q22) and t(8;21)(q22;q22)...
  24. pmc 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...
  25. 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
    ....
  26. pmc 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...
  27. pmc 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...
  28. pmc 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...
  29. pmc 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...
  30. pmc 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...
  31. pmc 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...
  32. pmc 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...
  33. pmc 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...
  34. ncbi BCR/ABL, mRNA translation and apoptosis
    D Perrotti
    Cell Death Differ 12:534-40. 2005