Middle East Journal of Cancer

Venetoclax Drives Significant Shifts in BIM and BCL-2 but not MCL-1 Gene Expression in a Mouse Model of Acute Lymphoblastic Leukemia

Document Type : Original Article(s)

Authors

Saeid Abroun
Kaveh Tari

Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

https://doi.org/10.30476/mejc.2025.104911.2214
Abstract
Background: T and B acute lymphoblastic leukemia (T, B-ALL) has seen improved survival rates with intensified chemotherapy, but therapy-resistant or refractory ALL remains a significant clinical challenge. This study examined the inhibitory effects of Venetoclax drug on the apoptosis gene to explore its potential as a novel therapeutic approach for treating human T, B-ALL.
Method: This was a preclinical experimental study. Firstly, samples were collected from a leukemia patient, followed by isolating blast cells that were injected into primary mice. The sample was obtained from mice in 1, 8 and 14 days; the CD45 human was quantified using flow cytometry to confirm the development of leukemia. Spleen cells from the primary mice were isolated and injected into the secondary mice. After 14 days, the Venetoclax drug was administered to the mouse models for 21 days. Subsequently, mouse spleen cells were gathered, and the expression of genes associated with apoptosis was assessed. A two-tailed t-test was performed to compare the expression of apoptotic genes between the control and Venetoclax-treated groups.
Results: Our findings indicated a decrease in the expression of the B-cell lymphoma 2 (BCL-2) gene, while the expression of the BCL-2-interacting mediator (BIM) of cell death gene exhibited an augmentation. The level of expression of the MCL-1 (Myeloid leukemia 1) gene did not display any significant divergence compared with the control group.
Conclusion: Venetoclax drug shows potential therapeutic potential in B and T-ALL, increasing BIM expression and decreasing BCL-2, but further investigation and clinical trial studies are needed.

Keywords

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Apoptosis
Subjects

Kaveh Tari (google scholar)

Saied Abroun (google scholar)

How to cite this article:

Tari K, Abroun S. Venetoclax Drives Significant Shifts in BIM and BCL-2 but not MCL-1 Gene Expression in a Mouse Model of Acute Lymphoblastic Leukemia. Middle East J Cancer. 2026; 17(1): 9-19. doi: 10.30476/mejc.2025.104911.2214

  1. Alperstein W, Boren M, McNeer JL. Pediatric acute lymphoblastic leukemia: From diagnosis to prognosis. Pediatr Ann. 2015;44(7):e168-74. doi: 10.3928/00904481-20150710-10. PMID: 26171706.
  2. Hossain MJ, Xie L, McCahan SM. Characterization of pediatric acute lymphoblastic leukemia survival patterns by age at diagnosis. J Cancer Epidemiol. 2014;2014:865979. doi: 10.1155/2014/865979. PMID: 25309596; PMCID: PMC4182848.
  3. Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet. 2020;395(10230):1146-62. doi: 10.1016/S0140-6736(19)33018-1. PMID: 32247396.
  4. Shahriari M, Shakibazad N, Haghpanah S, Ghasemi K. Extramedullary manifestations in acute lymphoblastic leukemia in children: a systematic review and guideline-based approach of treatment. Am J Blood Res. 2020;10(6):360-74. PMID: 33489446; PMCID: PMC7811904.
  5. Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370(9583):240-50. doi: 10.1016/S0140-6736(07)61126-X. PMID: 17658395.
  6. Pui CH. Precision medicine in acute lymphoblastic leukemia. Front Med. 2020;14(6):689-700. doi: 10.1007/s11684-020-0759-8. PMID: 33074527; PMCID: PMC9671279.
  7. Galli G, Vacher P, Ryffel B, Blanco P, Legembre P. Fas/CD95 signaling pathway in damage-associated molecular pattern (DAMP)-sensing receptors. Cells. 2022;11(9):1438.doi: 10.3390/cells11091438.PMID:35563744.PMCID:PMC9105874.
  8. Letai A. Apoptosis and cancer. Annu Rev Cancer Biol. 2017;1(1):275-94. doi:10.1146/annurev-cancerbio-050216-121933.
  9. Kiraz Y, Adan A, Kartal Yandim M, Baran Y. Major apoptotic mechanisms and genes involved in apoptosis. Tumour Biol. 2016;37(7):8471-86. doi: 10.1007/s13277-016-5035-9. PMID: 27059734.
  10. Wang Y, Zhong J, Bai J, Tong R, An F, Jiao P, et al. The application of natural products in cancer therapy by targeting apoptosis pathways. Curr Drug Metab. 2018;19(9):739-49. doi: 10.2174/1389200219666180511154722. PMID: 29749309.
  11. O'Neill KL, Huang K, Zhang J, Chen Y, Luo X. Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane. Genes Dev. 2016;30(8):973-88. doi: 10.1101/gad.276725.115. PMID: 27056669; PMCID: PMC4840302.
  12. Pang Z. The main BH3-only proteins in BCL-2 family. Highlights in Science, Engineering and Technology. 2023;36:276-82.doi: 10.54097/hset.v36i.5684.
  13. Ola MS, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 2011;351(1-2):41-58. doi: 10.1007/s11010-010-0709-x. PMID: 21210296.
  14. Warren CFA, Wong-Brown MW, Bowden NA. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis. 2019;10(3):177. doi: 10.1038/s41419-019-1407-6. PMID: 30792387; PMCID: PMC6384907.
  15. Banjara S, Suraweera CD, Hinds MG, Kvansakul M. The Bcl-2 family: ancient origins, conserved structures, and divergent mechanisms. Biomolecules. 2020;10(1):128. doi: 10.3390/biom10010128.PMID: 31940915.PMCID: PMC7022251.
  16. Adams JM, Cory S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 2018;25(1):27-36. doi: 10.1038/cdd.2017.161. PMID: 29099483; PMCID: PMC5729526.
  17. Pravdic Z, Vukovic NS, Gasic V, Marjanovic I, Karan-Djurasevic T, Pavlovic S, et al. The influence of BCL-2, BAX, and ABCB1 gene expression on prognosis of adult de novo acute myeloid leukemia with normal karyotype patients. Radiol Oncol. 2023;57(2):239-48. doi: 10.2478/raon-2023-0017. PMID: 37078709; PMCID: PMC10286896.
  18. Adams CM, Clark-Garvey S, Porcu P, Eischen CM. Targeting the Bcl-2 Family in B Cell Lymphoma. Front Oncol. 2019;8:636. doi: 10.3389/fonc.2018.00636. PMID: 30671383; PMCID: PMC6331425.
  19. Blombery P, Birkinshaw RW, Nguyen T, Gong JN, Thompson ER, Xu Z, et al. Characterization of a novel venetoclax resistance mutation (BCL-2 Phe104Ile) observed in follicular lymphoma. Br J Haematol. 2019;186(6):e188-91. doi: 10.1111/bjh.16069.PMID: 31234236.
  20. Del Poeta G, Postorino M, Pupo L, Del Principe MI, Dal Bo M, Bittolo T, et al. Venetoclax: Bcl-2 inhibition for the treatment of chronic lymphocytic leukemia. Drugs Today (Barc). 2016;52(4):249-60. doi: 10.1358/dot.2016.52.4.2470954. PMID: 27252989.
  21. Deeks ED. Venetoclax: first global approval. Drugs. 2016;76:979-87.doi: 10.1007/s40265-016-0596-x. PMID: 27260335.
  22. Orellana García LP, Ehmann F, Hines PA, Ritzhaupt A, Brand A. Biomarker and companion diagnostics-a review of medicinal products approved by the European Medicines Agency. Front Med (Lausanne). 2021;8:753187. doi: 10.3389/fmed.2021.753187. PMID: 34790681; PMCID: PMC8591033.
  23. Perini GF, Feres CCP, Teixeira LLC, Hamerschlak N. BCL-2 Inhibition as treatment for chronic lymphocytic leukemia. Curr Treat Options Oncol. 2021;22(8):66. doi: 10.1007/s11864-021-00862-z. PMID: 34110507.
  24. Itchaki G, Brown JR. The potential of venetoclax (ABT-199) in chronic lymphocytic leukemia. Ther Adv Hematol. 2016;7(5):270-87. doi: 10.1177/2040620716655350. PMID: 27695617; PMCID: PMC5026291.
  25. Mihalyova J, Jelinek T, Growkova K, Hrdinka M, Simicek M, Hajek R. Venetoclax: A new wave in hematooncology. Exp Hematol. 2018;61:10-25. doi: 10.1016/j.exphem.2018.02.002. PMID: 29477371.
  26. Smith VM, Dietz A, Henz K, Bruecher D, Jackson R, Kowald L, et al. Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma. Haematologica. 2020;105(8):2150-63. doi: 10.3324/haematol.2019.220525. PMID: 31601689; PMCID: PMC7395267.
  27. Merino D, Kelly GL, Lessene G, Wei AH, Roberts AW, Strasser A. BH3-mimetic drugs: Blazing the trail for new cancer medicines. Cancer Cell. 2018;34(6):879-91. doi: 10.1016/j.ccell.2018.11.004. PMID: 30537511.
  28. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. doi: 10.1182/blood-2018-08-868752. PMID: 30361262; PMCID: PMC6318429.
  29. Phillips DC, Xiao Y, Lam LT, Litvinovich E, Roberts-Rapp L, Souers AJ, et al. Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J. 2015;5(11):e368. doi: 10.1038/bcj.2015.88. Erratum in: Blood Cancer J. 2016;6:e403. doi: 10.1038/bcj.2016.12. PMID: 26565405; PMCID: PMC4670945.
  30. Peirs S, Matthijssens F, Goossens S, Van de Walle I, Ruggero K, de Bock CE, et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood. 2014;124(25):3738-47. doi: 10.1182/blood-2014-05-574566. PMID: 25301704.
  31. Ko TK, Chuah CT, Huang JW, Ng KP, Ong ST. The BCL-2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors. Oncotarget. 2014;5(19):9033.doi: 10.18632/oncotarget.1925.PMID: 25333252.PMCID: PMC4253416.
  32. Tari K, Nasimian A, Kazi JU, Abroun S. Venetoclax drug increases the apoptosis of T and B acute lymphoblastic leukemia cells by reducing the expression of BCL-2. Int J Mol Cell Med. 2023;12(3):229-41. doi: 10.22088/IJMCM.BUMS.12.3.229. PMID: 38751657; PMCID: PMC11092900.
  33. Canaani J, Frisch A, Pollyea DA, Schwartz M, Aumann S, Ganzel C, et al. Venetoclax-based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia. Eur J Haematol. 2023;111(3):365-72. doi: 10.1111/ejh.14015. PMID: 37254665.
  34. Khaw SL, Suryani S, Evans K, Richmond J, Robbins A, Kurmasheva RT, et al. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Blood. 2016;128(10):1382-95. doi: 10.1182/blood-2016-03-707414. PMID: 27343252; PMCID: PMC5016707.
  35. Pariury H, Fandel J, Bachl S, Ang KK, Markossian S, Wilson CG, et al. Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia. Haematologica. 2023;108(5):1272.doi: 10.3324/haematol.2022.281443. PMID: 36700399. PMCID: PMC10153511.
  36. Lacayo NJ, Pullarkat VA, Stock W, Jabbour E, Bajel A, Rubnitz J, et al. Safety and efficacy of venetoclax in combination with navitoclax in adult and pediatric relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Blood. 2019;134:285.doi: 10.1182/blood-2019-126977.
  37. Pullarkat VA, Lacayo NJ, Jabbour E, Rubnitz JE, Bajel A, Laetsch TW, et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer Discov. 2021;11(6):1440-53. doi: 10.1158/2159-8290.CD-20-1465. PMID: 33593877; PMCID: PMC9533326.

 

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