MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia.

Blood
Courtney JonesW L Carroll

Abstract

The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK ...Continue Reading

References

Jan 1, 1985·Annual Review of Genetics·K R Yamamoto
Apr 16, 1998·Proceedings of the National Academy of Sciences of the United States of America·I RogatskyM J Garabedian
Feb 28, 2002·Proceedings of the National Academy of Sciences of the United States of America·Annemieke de VriesTyler Jacks
Jan 2, 2003·Nature Reviews. Cancer·Julian Downward
Dec 23, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Rachelle DonnDavid Ray
Mar 9, 2007·Nature·Charles G MullighanJames R Downing
May 17, 2008·Molecular Endocrinology·Weiwei ChenMichael J Garabedian
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Oct 22, 2009·The FEBS Journal·Sebastien Cagnol, Jean-Claude Chambard
Jan 18, 2011·Expert Opinion on Investigational Drugs·Mark S Chapman, Jeffrey N Miner
May 24, 2011·The Journal of Endocrinology·George SchlossmacherAnne White
Jul 13, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jana HofRenate Kirschner-Schwabe
Sep 17, 2011·The Journal of Pediatrics·William L Carroll, Elizabeth A Raetz
Jan 12, 2013·Cell Death and Differentiation·M KracikovaS A Aaronson
Feb 5, 2013·Nature Genetics·Julia A MeyerWilliam L Carroll
Jul 6, 2014·British Journal of Haematology·Smita DandekarWilliam L Carroll

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Citations

Feb 9, 2016·European Journal of Medical Genetics·Hélène CavéAlain Verloes
Sep 25, 2016·Proceedings of the National Academy of Sciences of the United States of America·Sydney X Lu, Omar Abdel-Wahab
Dec 30, 2016·Nature Reviews. Clinical Oncology·Anas YounesJulie Vose
Feb 18, 2017·Nature Reviews. Drug Discovery·Avi AshkenaziAndrew J Souers
Feb 28, 2017·Médecine sciences : M/S·Souleymane Abdoul-AzizeJean-Pierre Vannier
Jun 27, 2017·Expert Review of Anticancer Therapy·Joanna PierroWilliam L Carroll
Oct 4, 2016·Therapeutic Advances in Hematology·Gilad Itchaki, Jennifer R Brown
Dec 3, 2016·Therapeutic Advances in Hematology·Valentín Ortíz-MaldonadoJulio Delgado
Oct 7, 2017·Nature Medicine·Adolfo A Ferrando, Carlos López-Otín
Oct 24, 2018·Endocrine Connections·Legh WilkinsonAnn Louw
Jan 6, 2018·Nature Reviews. Cancer·Markus Müschen
Aug 5, 2017·Expert Opinion on Drug Discovery·Rupal TripathiDolors Colomer
Apr 16, 2020·Pediatric Blood & Cancer·Yordan SbirkovVictoria Sarafian
Dec 17, 2017·Oncotarget·Estíbaliz Tamayo-OrbegozoSusana Larrucea
Aug 30, 2020·Paediatric Drugs·Sylwia JasinskiWilliam L Carroll
Dec 4, 2016·Hematology·Elizabeth A Raetz, David T Teachey
Feb 14, 2019·Scientific Reports·Isabel S JerchelMonique L den Boer
May 21, 2019·Global Pediatric Health·Aditya Srinivasan, Anand Gourishankar
Dec 23, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·William L CarrollElizabeth Raetz
Nov 11, 2019·Trends in Cancer·Matthew T WitkowskiIannis Aifantis

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