Venetoclax resistance in acute lymphoblastic leukemia is characterised by elevated mitochondrial exercise and might be overcome by co-targeting oxidative phosphorylation


  • Adams JM, Cory S. The Bcl-2 Protein Household: Arbiters of Cell Survival. Science. 1998;281:1322–6.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang DCS, Strasser A. BH3-Solely Proteins—Important Initiators of Apoptotic Cell Dying. Cell. 2000;103:839–42.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Roy MJ, Vom A, Czabotar PE, Lessene G. Cell dying and the mitochondria: therapeutic focusing on of the BCL ‐2 household‐pushed pathway. Br J Pharmacol. 2014;171:1973–87.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complicated Initiates an Apoptotic Protease Cascade. Cell. 1997;91:479–89.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fabbri G, Dalla-Favera R. The molecular pathogenesis of continual lymphocytic leukaemia. Nat Rev Most cancers. 2016;16:145–62.

    Article 
    PubMed 

    Google Scholar
     

  • Iqbal J, Neppalli VT, Wright G, Dave BJ, Horsman DE, Rosenwald A, et al. BCL2 Expression Is a Prognostic Marker for the Activated B-Cell–Like Sort of Diffuse Massive B-Cell Lymphoma. JCO. 2006;24:961–8.

    Article 
    CAS 

    Google Scholar
     

  • Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor exercise whereas sparing platelets. Nat Med. 2013;19:202–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, et al. Venetoclax in relapsed or refractory continual lymphocytic leukaemia with 17p deletion: a multicentre, open-label, section 2 examine. Lancet Oncol. 2016;17:768–78.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • DiNardo CD, Pratz Ok, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax mixed with decitabine or azacitidine in treatment-naive, aged sufferers with acute myeloid leukemia. Blood. 2019;133:7–17.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seyfried F, Demir S, Hörl RL, Stirnweiß FU, Ryan J, Scheffold A, et al. Prediction of venetoclax exercise in precursor B-ALL by practical evaluation of apoptosis signaling. Cell Dying Dis. 2019;10:571.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Richard-Carpentier G, Jabbour E, Quick NJ, Rausch CR, Savoy JM, Bose P, et al. Medical Expertise With Venetoclax Mixed With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia. Clin Lymphoma Myeloma Leuk. 2020;20:212–8.

    Article 
    PubMed 

    Google Scholar
     

  • Aumann S, Shaulov A, Haran A, Gross Even-Zohar N, Vainstein V, Nachmias B. The Rising Position of Venetoclax-Based mostly Remedies in Acute Lymphoblastic Leukemia. IJMS. 2022;23:10957.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blombery P. Mechanisms of intrinsic and purchased resistance to venetoclax in B-cell lymphoproliferative illness. Leuk Lymphoma. 2020;61:257–62.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Thijssen R, Roberts AW. Venetoclax in Lymphoid Malignancies: New Insights, Extra to Be taught. Most cancers Cell. 2019;36:341–3.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Meyer LH, Eckhoff SM, Queudeville M, Kraus JM, Giordan M, Stursberg J, et al. Early Relapse in ALL Is Recognized by Time to Leukemia in NOD/SCID Mice and Is Characterised by a Gene Signature Involving Survival Pathways. Most cancers Cell. 2011;19:206–17.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ryan J, Montero J, Rocco J, Letai A. iBH3: easy, fixable BH3 profiling to find out apoptotic priming in main tissue by move cytometry. Biol Chem. 2016;397:671–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D, et al. Drug-Induced Dying Signaling Technique Quickly Predicts Most cancers Response to Chemotherapy. Cell. 2015;160:977–89.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, et al. Differential Concentrating on of Prosurvival Bcl-2 Proteins by Their BH3-Solely Ligands Permits Complementary Apoptotic Perform. Mol Cell. 2005;17:393–403.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq information with DESeq2. Genome Biol. 2014;15:550.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment evaluation: A knowledge-based method for deciphering genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Raspotnig G, Fauler G, Jantscher A, Windischhofer W, Schachl Ok, Leis HJ. Colorimetric Willpower of Cell Numbers by Janus Inexperienced Staining. Anal Biochem. 1999;275:74–83.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhao W, Sachsenmeier Ok, Zhang L, Sult E, Hollingsworth RE, Yang H. A New Bliss Independence Mannequin to Analyze Drug Mixture Knowledge. SLAS Discov. 2014;19:817–21.

    Article 

    Google Scholar
     

  • Foucquier J, Guedj M. Evaluation of drug combos: present methodological panorama. Pharmacol Res Perspec. 2015;3:e00149.

    Article 

    Google Scholar
     

  • Ianevski A, Giri AK, Aittokallio T. SynergyFinder 2.0: visible analytics of multi-drug mixture synergies. Nucleic Acids Res. 2020;48:W488–93.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tausch E, Shut W, Dolnik A, Bloehdorn J, Chyla B, Bullinger L, et al. Venetoclax resistance and purchased BCL2 mutations in continual lymphocytic leukemia. Haematologica. 2019;104:e434–7.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moujalled DM, Brown FC, Chua CC, Dengler MA, Pomilio G, Anstee NS, et al. Acquired mutations in BAX confer resistance to BH3-mimetic remedy in acute myeloid leukemia. Blood. 2023;141:634–44.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Foight GW, Ryan JA, Gullá SV, Letai A, Keating AE. Designed BH3 Peptides with Excessive Affinity and Specificity for Concentrating on Mcl-1 in Cells. ACS Chem Biol. 2014;9:1962–8.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seyfried F, Stirnweiß FU, Niedermayer A, Enzenmüller S, Hörl RL, Münch V, et al. Synergistic exercise of mixed inhibition of anti-apoptotic molecules in B-cell precursor ALL. Leukemia. 2022;36:901–12.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ekstrand MI. Mitochondrial transcription issue A regulates mtDNA copy quantity in mammals. Hum Mol Genet. 2004;13:935–44.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Adebayo M, Singh S, Singh AP, Dasgupta S. Mitochondrial fusion and fission: The tremendous‐tune stability for mobile homeostasis. The FASEB Journal [Internet]. 2021 Jun [cited 2024 Jun 18];35. Out there from: https://onlinelibrary.wiley.com/doi/10.1096/fj.202100067R.

  • Kapoor I, Bodo J, Hill BT, Hsi ED, Almasan A. Concentrating on BCL-2 in B-cell malignancies and overcoming therapeutic resistance. Cell Dying Dis. 2020;11:941.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Queudeville M, Seyfried F, Eckhoff SM, Trentin L, Ulrich S, Schirmer M, et al. Speedy engraftment of human ALL in NOD/SCID mice entails poor apoptosis signaling. Cell Dying Dis. 2012;3:e364.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meyer LH, Karawajew L, Schrappe M, Ludwig WD, Debatin KM, Stahnke Ok. Cytochrome c–associated caspase-3 activation determines remedy response and relapse in childhood precursor B-cell ALL. Blood. 2006;107:4524–31.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Miyashita T, Reed J. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood. 1993;81:151–7.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Diaz-Flores E, Comeaux EQ, Kim KL, Melnik E, Beckman Ok, Davis KL, et al. Bcl-2 Is a Therapeutic Goal for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia. Most cancers Res. 2019;79:2339–51.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alford SE, Kothari A, Loeff FC, Eichhorn JM, Sakurikar N, Goselink HM, et al. BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Main Acute Lymphoblastic Leukemia Cells. Most cancers Res. 2015;75:1366–75.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frismantas V, Dobay MP, Rinaldi A, Tchinda J, Dunn SH, Kunz J, et al. Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Blood. 2017;129:e26–37.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mouttet B, Vinti L, Ancliff P, Bodmer N, Brethon B, Cario G, et al. Sturdy remissions in TCF3-HLF optimistic acute lymphoblastic leukemia with blinatumomab and stem cell transplantation. Haematologica. 2019;104:e244–7.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Place AE, Goldsmith Ok, Bourquin JP, Loh ML, Gore L, Morgenstern DA, et al. Accelerating Drug Improvement in Pediatric Most cancers: A Novel Part I Research Design of Venetoclax in Relapsed/Refractory Malignancies. Future Oncol. 2018;14:2115–29.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wei AH, Strickland SA, Hou JZ, Fiedler W, Lin TL, Walter RB, et al. Venetoclax Mixed With Low-Dose Cytarabine for Beforehand Untreated Sufferers With Acute Myeloid Leukemia: Outcomes From a Part Ib/II Research. JCO. 2019;37:1277–84.

    Article 
    CAS 

    Google Scholar
     

  • Punnoose EA, Leverson JD, Peale F, Boghaert ER, Belmont LD, Tan N, et al. Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in A number of Myeloma Fashions. Mol Most cancers Therapeutics. 2016;15:1132–44.

    Article 
    CAS 

    Google Scholar
     

  • Yue X, Chen Q, He J. Mixture methods to beat resistance to the BCL2 inhibitor venetoclax in hematologic malignancies. Most cancers Cell Int. 2020;20:524.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang Q, Riley-Gillis B, Han L, Jia Y, Lodi A, Zhang H, et al. Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia. Sig Transduct Goal Ther. 2022;7:51.

    Article 

    Google Scholar
     

  • Lin KH, Winter PS, Xie A, Roth C, Martz CA, Stein EM, et al. Concentrating on MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia. Sci Rep. 2016;6:27696.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang H, Nakauchi Y, Köhnke T, Stafford M, Bottomly D, Thomas R, et al. Built-in evaluation of affected person samples identifies biomarkers for venetoclax efficacy and mixture methods in acute myeloid leukemia. Nat Most cancers. 2020;1:826–39.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Su Y, Li X, Ma J, Zhao J, Liu S, Wang G, et al. Concentrating on PI3K, mTOR, ERK, and Bcl-2 signaling community exhibits superior antileukemic exercise towards AML ex vivo. Biochem Pharmacol. 2018;148:13–26.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Thijssen R, Tian L, Anderson MA, Flensburg C, Jarratt A, Garnham AL, et al. Single-cell multiomics reveal the dimensions of multilayered variations enabling CLL relapse throughout venetoclax remedy. Blood. 2022;140:2127–41.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thomalla D, Beckmann L, Grimm C, Oliverio M, Meder L, Herling CD, et al. Deregulation and epigenetic modification of BCL2-family genes trigger resistance to venetoclax in hematologic malignancies. Blood. 2022;140:2113–26.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chong SJF, Zhu F, Dashevsky O, Mizuno R, Lai JXH, Hackett L, et al. Hyperphosphorylation of BCL-2 household proteins underlies practical resistance to venetoclax in lymphoid malignancies. J Clin Investig. 2023;133:e170169.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Diepstraten ST, Younger S, La Marca JE, Wang Z, Kluck RM, Strasser A, et al. Lymphoma cells missing pro-apoptotic BAX are extremely immune to BH3-mimetics focusing on pro-survival MCL-1 however retain sensitivity to traditional DNA-damaging medicine. Cell Dying Differ. 2023;30:1005–17.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Choudhary GS, Al-harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 might be overcome by stopping PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Dying Dis. 2015;6:e1593.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sharma A, Nair R, Achreja A, Mittal A, Gupta P, Balakrishnan Ok, et al. Therapeutic implications of mitochondrial stress–induced proteasome inhibitor resistance in a number of myeloma. Sci Adv. 2022;8:eabq5575.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Carter JL, Hege Ok, Kalpage HA, Edwards H, Hüttemann M, Taub JW, et al. Concentrating on mitochondrial respiration for the remedy of acute myeloid leukemia. Biochem Pharmacol. 2020;182:114253.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guièze R, Liu VM, Rosebrock D, Jourdain AA, Hernández-Sánchez M, Martinez Zurita A, et al. Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies. Most cancers Cell. 2019;36:369–84.e13.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roca-Portoles A, Rodriguez-Blanco G, Sumpton D, Cloix C, Mullin M, Mackay GM, et al. Venetoclax causes metabolic reprogramming unbiased of BCL-2 inhibition. Cell Dying Dis. 2020;11:616.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tait SWG, Inexperienced DR. Mitochondria and cell signalling. J Cell Sci. 2012;125:807–15.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maycotte P, Marín-Hernández A, Goyri-Aguirre M, Anaya-Ruiz M, Reyes-Leyva J, Cortés-Hernández P. Mitochondrial dynamics and most cancers. Tumour Biol. 2017;39:101042831769839.

    Article 

    Google Scholar
     

  • Rossignol R, Gilkerson R, Aggeler R, Yamagata Ok, Remington SJ, Capaldi RA. Power Substrate Modulates Mitochondrial Construction and Oxidative Capability in Most cancers Cells. Most cancers Res. 2004;64:985–93.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gomes LC, Benedetto GD, Scorrano L. Throughout autophagy mitochondria elongate, are spared from degradation and maintain cell viability. Nat Cell Biol. 2011;13:589–98.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Youle RJ, Van Der Bliek AM. Mitochondrial Fission, Fusion, and Stress. Science. 2012;337:1062–5.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen X, Glytsou C, Zhou H, Narang S, Reyna DE, Lopez A, et al. Concentrating on Mitochondrial Construction Sensitizes Acute Myeloid Leukemia to Venetoclax Therapy. Most cancers Discov. 2019;9:890–909.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang G, Frederick DT, Wu L, Wei Z, Krepler C, Srinivasan S, et al. Concentrating on mitochondrial biogenesis to beat drug resistance to MAPK inhibitors. J Clin Investig. 2016;126:1834–56.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin CS, Liu LT, Ou LH, Pan SC, Lin CI, Wei YH. Position of mitochondrial perform within the invasiveness of human colon most cancers cells. Oncol Rep. [Internet]. 2017 Nov [cited 2023 Feb 6]; Out there from: http://www.spandidos-publications.com/10.3892/or.2017.6087

  • Nayak AP, Kapur A, Barroilhet L, Patankar MS. Oxidative Phosphorylation: A Goal for Novel Therapeutic Methods In opposition to Ovarian Most cancers. Cancers. 2018;10:337.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bajpai R, Sharma A, Achreja A, Edgar CL, Wei C, Siddiqa AA, et al. Electron transport chain exercise is a predictor and goal for venetoclax sensitivity in a number of myeloma. Nat Commun. 2020;11:1228.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hot Topics

    Related Articles