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Acid ceramidase is upregulated in AML and represents a novel therapeutic target

dc.contributor.authorTan, Su-Fern
dc.contributor.authorLiu, Xin
dc.contributor.authorFox, Todd E.
dc.contributor.authorBarth, Brian M.
dc.contributor.authorSharma, Arati
dc.contributor.authorTurner, Stephen D.
dc.contributor.authorAwwad, Andy
dc.contributor.authorDewey, Alden
dc.contributor.authorDoi, Kenichiro
dc.contributor.authorSpitzer, Barbara
dc.contributor.authorShah, Mithun Vinod
dc.contributor.authorMorad, Samy A.F.
dc.contributor.authorDesai, Dhimant
dc.contributor.authorAmin, Shantu
dc.contributor.authorZhu, Junjia
dc.contributor.authorLiao, Jason
dc.contributor.authorYun, Jong
dc.contributor.authorKester, Mark
dc.contributor.authorClaxton, David F.
dc.contributor.authorWang, Hong-Gang
dc.contributor.authorCabot, Myles C.
dc.contributor.authorSchuchman, Edward H.
dc.contributor.authorLevine, Ross L.
dc.contributor.authorFeith, David J.
dc.contributor.authorLoughran, Thomas P. Jr.
dc.date.accessioned2020-04-28T16:17:05Z
dc.date.available2020-04-28T16:17:05Z
dc.date.issued2016-12-13
dc.description.abstractThere is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML.en_US
dc.identifier.doi10.18632/oncotarget.13079
dc.identifier.urihttp://hdl.handle.net/10342/8448
dc.titleAcid ceramidase is upregulated in AML and represents a novel therapeutic targeten_US
dc.typeArticleen_US
ecu.journal.issue50en_US
ecu.journal.nameOncotargeten_US
ecu.journal.pages83208-83222en_US
ecu.journal.volume7en_US

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