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Fatty Acid Metabolism and Desaturation in the Pathogenesis of Leukemic Stem Cells in Acute Myeloid Leukemia

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Fatty Acid Metabolism and Desaturation in the Pathogenesis of Leukemic Stem Cells in Acute Myeloid Leukemia Fatty acid metabolism and desaturation in the pathogenesis of leukemic stem cells in Acute Myeloid Leukemia Rachel Culp-Hill1,2, Courtney Jones3, Brett Stevens3, Daniel Pollyea3, Shanshan Pei3, Craig Jordan3, Angelo D’Alessandro1,2 1Graduate Program in Structural Biology and Biochemistry, 2Department of Biochemistry & Molecular Genetics, 3Blood Cancer and BMT Program, Division of Hematology, University of Colorado AMC, Aurora, CO, USA Abstract Ven/Aza targets de novo LSC metabolism… Dysregulation of fatty acid desaturation in relapse p53 controls FA metabolism and desaturation p53 knockout in an AML cell line results in Background: Acute myeloid leukemia (AML) is a cancer of bone marrow- LSCs blasts 510 06 Vehicle Ven+Aza 1.210 7 Saturated Lipids Unsaturated Lipids derived blood cells, where leukemic blasts build up and block function and Newly diagnosed (de novo) ALA ALA increased unsaturated fatty acids, including 1.0 10 7 development of myeloid progenitors. Conventional therapy eliminates bulk LSCs uptake amino acids 410 06 ARG ARG Diagnosis docosapentaenoic acid (22:5) and tumor cells but leukemic stem cells (LSCs) survive, leading to disease ASP more quickly than leukemic 6 ASP 8.010 Relapse docosahexaenoic acid (22:6). Loss of p53 progression and relapse. LSCs uniquely rely on oxidative phosphorylation CYS blasts, and when amino GLU 310 06 6 increases unsaturated fatty acids, similarly (OXPHOS), metabolically driven by amino acid and fatty acid metabolism. C-C GLN 6.010 acids are removed, 06 GLU HIS 210 to the relapsed AML phenotype. 4.010 6 Aim: We have successfully targeted amino acid metabolism in LSCs, but the GLN OXPHOS is reduced. LEU HIS 110 06 mechanisms controlling fatty acid metabolism are yet unknown. Our primary De novo LSCs use amino LYS 2.010 6 LYS p53 knockout also results in increases in all objective is to understand how fatty acids fuel OXPHOS in LSCs. acids to fuel OXPHOS. MET MET 0 PHE 0 intermediates of the mevalonate pathway, PHE FA(15:0) FA(16:0) PE(45:8) PC(42:4) PI(43:10) PIP(53:5) PEt(44:7) LPC(16:0) LPC(18:0) resulting from production of Acetyl-CoA from LPC(18:1) LPC(18:2) PRO PMe(26:5) MGMG(2:0) PMe(40:4p) Results and Discussion: LSCs in relapsed/refractory patients display PRO GM3(d34:1) PE(18:0/16:0) PC(16:0/16:0) CerG2(d34:5) CerG2(d36:6) PE(15:1/22:6) PE(24:1/20:4) PS(20:3/20:4) PS(20:4/20:4) PC(17:1/18:2) PIP(18:0/18:0) PG(24:6/20:4) PG(25:2/18:1) PEt(18:1/22:5) SM(d20:0/16:0) SM(d20:0/16:0) SM(d22:1/22:4) When de novo LSCs are PIP2(17:1/19:3) SER SQDG(18:1/18:2) dMePE(18:1/13:1) increased fatty acid metabolism, driving OXPHOS and LSC survival. SER dMePE(15:2/22:5) fatty acids. CL(21:2/20:4/22:6/22:2) Unsaturated fatty acids are oxidized more rapidly than saturated, so THR treated with a combination THR CL(18:2/18:2/18:2/18:2) TRP Docosanoic Acid (22:0) Docosapentaenoic Acid (22:5) Docosahexaenoic Acid (22:6) TRP 04 increased fatty acid desaturase (FADS) activity fuels OXPHOS more than of Venetoclax (BCL-2 610 05 610 04 * 510 *** VAL VAL overall fatty acid metabolism. Similar increases in fatty acid desaturation inhibitor) and Azacitidine 410 04 410 05 410 04 occur in cases of p53 loss in AML. Successful inhibition of OXPHOS is 310 04 /min) (DNA hypomethylator), 2 04 O 210 dependent on p53-driven apoptotic pathways, and p53 is a tight regulator 210 05 210 04 amino acid depletion is pM 110 04 Relative abundance Relative Relative abundance Relative of lipid metabolism. Therefore, loss of p53 function in AML may result in loss abundance Relative recapitulated. 0 0 0 of FADS inhibition and promotion of fatty acid desaturation. Diagnosis Relapse Diagnosis Relapse Diagnosis Relapse Ven/Aza metabolically Conclusion: Relapsed/refractory LSCs upregulate fatty acid desaturation targets de novo LSCs by Relapse LSCs have significantly increased unsaturated fatty acids compared to through increased FADS activity to maintain OXPHOS as a mechanism for impairing amino acid saturated fatty acids. Interestingly, docosapentaenoic acid (22:5) and survival. Additionally, loss of p53 function in AML may result in loss of ( consumptionOxygen Vehicle Ven/Aza import and metabolism. docosahexaenoic acid (22:6) are the end products of a pathway to produce inhibition of FADS1, increasing fatty acid desaturation. As unsaturated fatty highly unsaturated fatty acids using fatty acid desaturases FADS1 and FADS2. acids are oxidized more quickly than saturated, this may allow relapse LSCs NT TP53 TP53 to compensate for a loss of amino acids resulting from Ven/Aza. FADS1 FADS2 … but relapse LSCs can metabolically compensate 1.0 1.0 Leukemic Stem lowest 25% (N=44) lowest 25% (N=44) l l low 25% (N=44) low 25% (N=44) Methods a a 0.8 0.8 v v high 25% (N=44) high 25% (N=44) i Cells (LSCs) i v Upon treatment with Ven/Aza, relapse LSCs v highest 25% (N=44) highest 25% (N=44) r r u u 0.6 0.6 s s are significantly more viable than de novo n n o o i i 0.4 0.4 t t c LSCs. Ven/Aza isn’t affecting relapse LSCs in c a Leukemic a r r F Unsaturated F 0.2 0.2 Blasts the same way as de novo LSCs. p = 0.0036 p = 0.4229 Fatty Acids Upon depletion of AAs, relapse LSCs show 0.0 0.0 0 25 50 75 100 125 150 0 25 50 75 100 125 150 increased levels of fatty acids. Addition of EFS (months) EFS (months) Ven/Aza fatty acid translocase (CD36) inhibitor SSO Vanquish UHPLC Traditional Increased expression of FADS1 and FADS2 is associated with poor prognosis in Kinetex C18 column - 2.1x150mm, 1.7µ Energetic Amino re-sensitizes relapse LSCs to Ven/Aza. Chemotherapy patients with AML, suggesting FADS activity contributes to LSC survival. ▪ 3 min. isocratic elution Pathways Acids Relapse LSCs may compensate for amino acid Polyamines, basic AAs ▪ 5/9 min. gradient elution Sugars, carboxylic acids Acquity HSS T3 column - 2.1x150mm, 1.8µ Genetic Inhibition Pharmacologic Inhibition Aromatic AAs ▪ 17 min. gradient elution Resistant LSCs (OXPHOS) loss by upregulating fatty acid metabolism. **** *** Phosphates, Nucleosides Q Exactive Mass Spectrometer **** Fatty Acids Full MS mode, 60-900m/z, 125-1500m/z *** 100 Disease 75 e v i l Relapse A Future Directions % 50 ▪ Determine the effects of Ven/Aza on lipid desaturation and fatty acid metabolism 25 ▪ Perform p53 knockdown in primary patient LSCs to confirm aberrant lipid desaturation 1. Jones CL, et al. Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells. Cancer Cell. 2019. 0 Scr Scr FADS2 FADS2 ▪ Genetically and pharmacologically inhibit FADS in the context of p53 loss 2. Pollyea DA, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients Vehicle Ven/aza Vehicle Ven/aza Diagnosis Relapse with acute myeloid leukemia. Nature Medicine. 2018. ▪ Further explore the role of p53 and the proteins controlling its function in the 3. Nechiporuk T, et al. Cancer Discovery. The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Both genetic and pharmacologic inhibition of FADS, when combined with ven/aza, mechanism of survival for relapse LSCs Inhibition in AML Cells. 2019. 4. Moon et al. Cell. p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression. 2019. successfully eliminate LSCs from relapse AML patients. ▪ Explore metabolic progression from MDS to AML.
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