Genomes and Genes
Role of RNA-Binding Proteins in BCR/ABL Leukemogenesis
Principal Investigator: D Perrotti
Affiliation: The Ohio State University
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
- BCR/ABL, mRNA translation and apoptosisD Perrotti
Cell Death Differ 12:534-40. 2005
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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...
- Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemiasDanilo 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...
- Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-kappaB-dependent DNA methyltransferase activity in acute myeloid leukemiaShujun 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...
- Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesisAnna 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...
- The PP2A inhibitor SET regulates natural killer cell IFN-gamma productionRossana 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...
- FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphomaQing 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...
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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...
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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...
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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...
- High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiationJi 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...
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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....
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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...
- Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B StudyPeter 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...
- CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but differ in their antileukemic activitiesYoung 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...
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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....
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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...
- The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET proteinPaolo 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...
- Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patientsA 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...