4. 3. 2. 1. to acids inhibition survival through Conclusion of of dependent occur overall increased Unsaturated increased Results objective mechanisms Aim (OXPHOS), progression tumor development derived Background Moon et al. Cell. p53 Represses the MevalonatePathway Inhibitionto Mediatein AML Tumor Cells.Suppression. 2019. 2019. NechiporukT, et al. Cancer Discovery. The TP53 Apoptoticwith acuteNetwork myeloid Is leukemia. a PrimaryNature Mediator Medicine. ofPollyea Resistance2018. DA, etto al.BCL2 Venetoclax with Jones CL, et al. Inhibitionof Amino Acid MetabolismSelectively Targets HumanLeukemia Stem Cells. Cancer Cell. 2019. compensate FADS lipid : We are in cells . fatty metabolism increased blood inhibition and Additionally, is of cases oxidized have Chemotherapy fatty fatty : to on metabolically Leukemic Stem : controlling Resistant LSCs and Traditional FADS but Relapsed/refractory fatty Cells Cells (LSCs) of acid Acute understand Leukemic p Discussion for cells, successfully Disease Relapse Blasts 53 of acid myeloid relapse 1 leukemic acid and a - FADS , . metabolism more driven p acids loss myeloid Therefore, increasing where 53 desaturase promotion loss fatty azacitidine metabolism, of . quickly activity Fatty acid metabolism and desaturation in the pathogenesis of leukemic inAcuteMyeloidFatty stemcells desaturationacid metabolismandLeukemia pathogenesisin the of loss driven how : progenitors are apoptotic LSCs amino targeted of stem leukemic LSCs acid leukemia fatty in . disrupts energy metabolismand targets leukemiastem cells in patients p fatty loss oxidized Similar Abstract by uniquely 53 than of AML to acids metabolism cells (FADS) in LSCs Unsaturated amino of Fatty Acids acids fatty maintain function pathways, acid . blasts amino driving . relapsed/refractory saturated, p Conventional (AML) resulting (LSCs) Successful increases 53 upregulate acid fuel more rely activity 1 acid desaturation Graduate Program BiologyStructural in and Biochemistry, function build acid Pathways (OXPHOS) Energetic in OXPHOS are OXPHOS is desaturation OXPHOS on and survive, and rapidly from AML a this metabolism up in fuels yet oxidative inhibition cancer fatty in p may fatty therapy fatty and Ven/Aza 53 unknown AML may . in OXPHOS As leading as acid than and Rachel Culp Rachel is allow LSCs block . acid acid of unsaturated may a patients a result phosphorylation of in eliminates metabolism mechanism tight bone . . . saturated, LSC LSCs, relapse Our function desaturation desaturation OXPHOS result Ven/Aza to more Amino in Acids regulator marrow survival primary disease display but loss in fatty LSCs than bulk and . loss the for of so is - . - Hill … but relapse LSCs can metabolically compensate 1,2 LSCs blasts LSCs Ven/Aza targets , Courtney Jones VAL TRP THR SER PRO PHE MET LYS HIS GLN GLU C CYS ASP ARG ALA - C Newly( diagnosed treated with a combination with a treated more quickly than leukemicthan quickly more 2 import metabolism. and import inhibitor) and inhibitor) De novoDe LSCs uptakeamino acids targets targets Ven/Aza metabolically Department of Biochemistry & Molecular Molecular Genetics,& Biochemistry of Department When acids to fuel fuel to OXPHOS.acids blasts, and when when blasts,amino and amino acid depletion is depletion amino acid (DNA impairing amino acid impairing of of OXPHOSis reduced. acids are removed,are acids de novo de Venetoclax RelapseLSCs may compensate for aminoacid recapitulated. LSCs. loss by upregulatingfatty acid metabolism. Upon treatment with Ven/Aza, treatment Upon LSCs relapse fatty acid translocase (CD36) inhibitor SSO SSO inhibitor (CD36) acidtranslocase fatty hypomethylator de novode increased levels of fatty acids. Addition of of acids.Addition fatty levelsincreased of Upon depletion of AAs,LSCs showrelapse of depletion Upon are significantly more viable than viablemore significantlyare de de novo 3 LSCs use amino amino use LSCs re , Stevens Brett Ven/Aza in LSCs isn’t relapse affecting - sensitizes relapse LSCs to to Ven/Aza.LSCs relapse sensitizes the same way as the waysame Azacitidine LSCs are LSCs LSCs by LSCs (BCL LSC metabolism… de novode - 2 ), )
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NT p53 controls FA metabolism and desaturation TP53 Fatty Acids Phosphates,Nucleosides AromaticAAs Sugars,carboxylic acids Polyamines, basicAAs TP53 1,2 Future Directions Methods resultingfrom production of Acetyl increasesunsaturated fatty acids, similarly increasedunsaturated fatty acids, including p53knockout also resultsin increasesin all docosahexaenoicacid (22:6). intermediates of the mevalonatepathway, p53knockout in an AML cell line resultsin Full Full MS mode, 60 Q AcquityHSS T3 Kinetex C18column VanquishUHPLC docosapentaenoic to the relapsed AML phenotype. Exactive ▪ ▪ ▪ 17 min. gradientelution 5/9 min. gradientelution 3 min. isocraticelution Mass Spectrometer Mass column fattyacids. - 900m/z, 125900m/z, - 2.1x150mm, 1.7µ - 2.1x150mm, 1.8 acid(22:5) and - 1500m/z Loss p53of - CoAfrom µ