Role of the BCL-2 Pathway in Acute Myeloid Leukemia

Sponsored Content by AbbVie
Published: Friday, Nov 22, 2019

blood cellsDAcute myeloid leukemia (AML) is one of the most common types of leukemia and has the lowest 5-year relative survival rate, making it one of the most devastating hematologic cancers.1,2 Not only does AML progress rapidly and with high intensity, but, over the last few decades, there have been limited changes in the management of the disease. As the median age at diagnosis is 68, AML is primarily a disease of the elderly, who are more likely to have comorbidities, and who generally have a poorer prognosis, compared to their younger counterparts.3,4

Some of the differences in older patients with AML may be explained, in part, by the fact that they are more likely to harbor deleterious mutations—changes in their genetic signature that may drive disease pathophysiology.5 Compounding the challenge, patient age may affect the ability to tolerate intensive treatment that defines the standard of care.

“Given the low survival rates in the patient population most often affected by AML – those over the age of 60 – additional approaches aimed at improving outcomes for these patients are needed,” explained Mohamed Zaki, M.D., Ph.D., vice president, global head of hematology development, AbbVie. “For older patients, non-chemotherapy options are needed, as this patient population is less likely to be able to tolerate intensive chemotherapy and have shown to derive less benefits from the treatment compared to younger patients.”

Prognosis is influenced by individual patient characteristics such as age, presence of comorbid conditions affecting performance status, and preexisting myelodysplasia. This is particularly true of elderly patients with AML.4,5,6

The AML landscape has continued to evolve in recent years, as researchers and investigators have developed a far better understanding of the biological underpinnings of the disease. This has led to the discovery and understanding of biomarkers and diverse signaling pathways, which have prompted the recent emergence of a host of targeted, non-chemotherapeutic treatment modalities.

“The scientific communities’ knowledge of how cancers develop and proliferate has been integral to continued research across many types of cancers, including AML,” continued Dr. Zaki. “One of the most recent research advances came from our understanding of how apoptosis (programmed cell death) plays a role in AML.”

Apoptosis is a process which normally facilitates the cellular turnover required to maintain tissue homeostasis. Resistance to apoptosis is a hallmark of many cancers, including AML. Overexpression of pro-survival BCL-2 family regulator proteins is an important driver of resistance to cell death in AML.7 The BCL-2 family of proteins—comprising an array of pro-death (e.g., BAX, BAK) and pro-survival (e.g., BCL-2, BCL-XL) proteins—play a key role in regulating apoptosis. To maintain survival, cells require enough pro-survival members to bind and sequester pro-apoptotic at the outer mitochondrial membrane. When changes in expression tip the balance in favor of pro-apoptotic BCL-2 family members, they are then able to form pores in the mitochondrial membrane, releasing a molecule called cytochrome C, a critical event that leads to programmed cell death.7,8

One post hoc translational study found that approximately 80% of AML patient samples overexpressed a pro-survival BCL-2 family protein.7,9,10 Another study found that BCL-2 proteins were overexpressed in about 87% of newly diagnosed AML cases and in 100% of patients at relapse.11 While overexpression is an important factor, it is also noteworthy that in many cases, the BCL-2 found in AML cells is bound to pro-death proteins. The relatively large pool of sequestered pro-death proteins are said to leave such AML cells “primed” for apoptosis, making BCL-2 an attractive therapeutic target among AML researchers.12

“We’re in the midst of a revolution in the AML field based on the knowledge researchers have gained about the AML mechanism of disease,” Dr. Zaki added. “Among the most promising discoveries has been the BCL-2 pathway and its role in AML. Because of the survival advantage that BCL-2 family signaling confers to AML, this protein family has been an attractive research target.”

For more information about the BCL-2 pathway in AML, visit www.bcl2familyinaml.com.

References

  1. Cancer.Net (2019). “Leukemia - Acute Myeloid - AML: Statistics”. https://www.cancer.net/cancer-types/leukemia-acute-myeloid aml/statistics#targetText=This%20year%2C%20an%20estimated%2021%2C450,most%20cases%20occur%20in%20adults. Accessed October 24, 2019.
  2. American Cancer Society (2019). Cancer Facts & Figures 2019. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed October 10, 2019.
  3. National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Cancer stat facts: leukemia—acute myeloid leukemia (AML). https://seer.cancer.gov/statfacts/html/amyl.html. Accessed November 6, 2018.
  4. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152.
  5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V3.2018. National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed November 6, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org.
  6. Yogarajah M, Stone RM. A concise review of BCL-2 inhibition in acute myeloid leukemia. Expert Rev Hematol. 2018;11(2):145-154.
  7. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3(4):279-296.
  8. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.
  9. Banker DE, Groudine M, Norwood T, Appelbaum FR. Measurement of spontaneous and therapeutic agent-induced apoptosis with BCL-2 protein expression in acute myeloid leukemia. Blood. 1997;89(1):243-255.
  10. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
  11. L Bensi, R Longo, A Vecchi, et al. BCL-2 Oncoprotein Expression In Acute Myeloid Leukemia. Haematologica. January 1995 80: 98-102.
  12. Konopleva M, Letai A. BCL-2 inhibition in AML: an unexpected bonus?. Blood. 2018;132(10):1007–1012. doi: https://doi.org/10.1182/blood-2018-03-828269.


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