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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