Lineage of origin in rhabdomyosarcoma informs pharmacological response
Por:
Abraham, J, Nunez-Alvarez, Y, Hettmer, S, Carrio, E, Chen, HIH, Nishijo, K, Huang, ET, Prajapati, SI, Walker, RL, Davis, S, Rebeles, J, Wiebush, H, McCleish, AT, Hampton, ST, Bjornson, CRR, Brack, AS, Wagers, AJ, Rando, TA, Capecchi, MR, Marini, FC, Ehler, BR, Zarzabal, LA, Goros, MW, Michalek, JE, Meltzer, PS, Langenau, DM, LeGallo, RD, Mansoor, A, Chen, Y, Suelves, M, Rubin, BP and Keller, C
Publicada:
15 jul 2014
Resumen:
Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.
Filiaciones:
Abraham, J:
Oregon Hlth & Sci Univ, Pape Family Pediat Res Inst, Pediat Canc Biol Program, Dept Pediat, Portland, OR 97239 USA
Nunez-Alvarez, Y:
Germans I Trias Pujol Hlth Sci Res Inst IGTP, IMPPC, Badalona 08916, Spain
Hettmer, S:
Harvard Univ, Howard Hughes Med Inst, Harvard Stem Cell Inst, Joslin Diabet Ctr,Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Pediat Hematol Oncol, Boston, MA 02115 USA
Carrio, E:
Germans I Trias Pujol Hlth Sci Res Inst IGTP, IMPPC, Badalona 08916, Spain
Chen, HIH:
Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA
Nishijo, K:
Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA
Huang, ET:
Oregon Hlth & Sci Univ, Pape Family Pediat Res Inst, Pediat Canc Biol Program, Dept Pediat, Portland, OR 97239 USA
Prajapati, SI:
Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA
Walker, RL:
Natl Canc Inst, Oncogen Sect, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD 20877 USA
Davis, S:
Natl Canc Inst, Oncogen Sect, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD 20877 USA
Rebeles, J:
Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA
Wiebush, H:
Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA
McCleish, AT:
Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA
Hampton, ST:
Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA
Bjornson, CRR:
Stanford Univ, Dept Neurol, Dept Neurol Sci, Glenn Labs Biol Aging, Palo Alto, CA 94304 USA
Brack, AS:
Stanford Univ, Dept Neurol, Dept Neurol Sci, Glenn Labs Biol Aging, Palo Alto, CA 94304 USA
Wagers, AJ:
Harvard Univ, Howard Hughes Med Inst, Harvard Stem Cell Inst, Joslin Diabet Ctr,Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
Capecchi, MR:
Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA
Marini, FC:
Wake Forest Univ, Bowman Gray Sch Med, Inst Regenerat Med, Winston Salem, NC 27157 USA
Ehler, BR:
Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA
Zarzabal, LA:
Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA
Goros, MW:
Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA
Michalek, JE:
Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA
Meltzer, PS:
Natl Canc Inst, Oncogen Sect, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD 20877 USA
Langenau, DM:
Massachusetts Gen Hosp, Ctr Canc Res, Dept Pathol, Charlestown, MA 02129 USA
LeGallo, RD:
Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA
Mansoor, A:
Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97239 USA
Chen, Y:
Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA
:
Germans I Trias Pujol Hlth Sci Res Inst IGTP, IMPPC, Badalona 08916, Spain
Rubin, BP:
Cleveland Clin Fdn, Lerner Res Inst, Taussig Canc Ctr, Dept Anat Pathol,Dept Mol Genet, Cleveland, OH 44195 USA
Keller, C:
Oregon Hlth & Sci Univ, Pape Family Pediat Res Inst, Pediat Canc Biol Program, Dept Pediat, Portland, OR 97239 USA
Green Published, gold
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