BCL-2 Family Pathway

Overview

The BCL-2 family is composed of anti- and pro-apoptotic proteins that function to regulate the intrinsic pathway of apoptosis.1,2

  • Anti-apoptotic members: BCL-2, BCL-XL, BFL-1/A1, BCL-W and MCL-13
  • Pro-apoptotic members: BAX, BAK, BIM, BID, BOK, BAD, PUMA and NOXA3,4

When working in concert, these proteins regulate apoptosis to maintain normal cellular homeostasis.1,5

The principal function of the BCL-2 protein is to bind and sequester pro-apoptotic proteins, preventing them from initiating apoptosis.2,6

Implications in cancer

  • Acquired resistance to apoptosis is a hallmark of most, if not all types of cancer.7
  • Overexpression of BCL-2 disrupts the dynamic balance of anti- and pro-apoptotic proteins, which may promote cancer cell survival.2
  • This overexpression is seen in a wide variety of hematologic malignancies and solid tumors.2
  • The role BCL-2 plays in tumor survival makes it a rational target for therapeutic intervention.5,8

Acute Myeloid Leukemia (AML) / Myelodysplastic Syndromes (MDS)

  • The BCL-2 protein is overexpressed in a high proportion of AML cases.9,10
  • Elevated levels of BCL-2 correlate with poor prognosis and chemoresistance.11-14
  • A high number of BCL-2 addicted cell lines and patient samples are sensitive to selective BCL-2 inhibition.15

Chronic Lymphocytic Leukemia (CLL)

  • Relatively high levels of BCL-2 expression are documented in 95% of CLL cases compared to normal peripheral blood lymphocytes.16
  • Impaired apoptosis caused by BCL-2 overexpression results in the accumulation of mature neoplastic lymphocytes in the blood and other lymphoid organs.17

Non-Hodgkin Lymphoma (NHL)

Mantle Cell Lymphoma (MCL)

  • The BCL-2 pathway is commonly deregulated in MCL cases and the BCL-2 gene is often amplified.18,19

Follicular Lymphoma (FL)

  • Approximately 85% of patients with FL have t(14;18), a translocation between chromosomes 14 (Ig) and 18 (BCL-2).20
  • BCL-2 protein overexpression is detected in over 60% of FL cases.12
  • The vast majority of patients with BCL-2 protein overexpression develop chemoresistance and experience higher relapse rates compared with BCL-2-negative patients.

Diffuse Large B-Cell Lymphoma (DLBCL)

  • BCL-2 protein overexpression is detected in up to 90% of DLBCL cases.12,21
  • In approximately 60% of cases, BCL-2 and MYC are coexpressed ("double-hit" or "double-positive" DLBCL); expressing both MYC and BCL-2 proteins correlates with an aggressive clinical course and a poor outcome.21

Multiple Myeloma (MM)

  • BCL-2 is highly expressed in a subset of myeloma cells, including t(11;14) translocated MM.22-24
  1. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590-8607.
  2. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3:279-296.
  3. Trudel S, Stewart AK, Li Z, et al. The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res. 2007;13(2):621-629.
  4. Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012;30(25):3127-3135.
  5. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324-1337.
  6. Leverson JD, Phillips DC, Mitten MJ, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Cancer. 2015;7(279):279ra40.
  7. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
  8. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15(1):49-63.
  9. Campos L, Rouault JP, Sabido O, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993;81(11):3091-3096.
  10. Mehta SV, Shukla SN, Vora HH. Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: its correlation with FLT3. Neoplasma. 2013;60(6):666-675.
  11. Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A. The role of apoptosis, proliferation, and the Bcl–2–related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood. 2000;96(12):3932-3938.
  12. Mahmoud HM, El-Sakhawy YN. Significance of Bcl-2 and Bcl-6 immunostaining in B-non Hodgkin's lymphoma. Hematol Rep. 2011;3(3):e26.
  13. Schimmer AD. Novel therapies targeting the apoptosis pathway for the treatment of acute myeloid leukemia. Curr Treat Options Oncol. 2007;8(4):277-286.
  14. Del Poeta G, Venditti A, Del Principe MI, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood. 2002;101(6):2125-2131.
  15. Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362-375.
  16. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 1993;82(6):1820-1828.
  17. Anderson MA, Huang D, Roberts A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol. 2014;51(3):219-227.
  18. Perez-Galan P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011;117(1):26-38.
  19. Parekh S, Weniger MA, Wiestner A. New molecular targets in mantle cell lymphoma. Semin Cancer Biol. 2011;21(5):335-346.
  20. Freedman A. Follicular lymphoma: 2018 update on diagnosis and management. Am J Hematol. 2018;93(2):296-305.
  21. Wang J, Zhou M, Xu J, Chen B, Ouyang J. Combination of BCL-2 and MYC protein expression improves high-risk stratification in diffuse large B-cell lymphoma. Onco Targets Ther. 2015;8:2645-2650.
  22. Bodet L, Gomez-Bougie P, Touzeau C, et al. ABT-737 is highly effective against molecular subgroups of multiple myeloma. Blood. 2011;118(14):3901-3910.
  23. Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401-2409.
  24. Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28:210-212.

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