MCL-1

Overview

Myeloid leukemia cell differentiation protein (myeloid cell leukemia-1; MCL-1) is a pro-survival member of mitochondrial (anti-)apoptotic B-cell lymphoma 2 (BCL-2) family proteins and a key regulator of mitochondrial homeostasis. 1-4

MCL-1 has a number of functions and features that make it unique among the anti-apoptotic BCL-2 family members.3

  • MCL-1 is essential for early embryogenesis as well as the development and maintenance of lymphocytes, neurons, synovial fibroblasts, and hematopoietic stem cells.3

The balance between pro- and anti-apoptotic BCL-2 family proteins occurs at the mitochondrion where the effectors of apoptosis, BAK and BAX promote mitochondrial outer membrane permeabilization (MOMP) and apoptotic cell death when activated by BH3-only activators like BIM, BID, and PUMA.2

  • Anti-apoptotic proteins (BCL-2, MCL-1, BCL-XL, and BCL-W) derail this process by sequestering the effector and activator proteins and preventing activation of mitochondrial outer membrane permeabilization (MOMP).2

MCL-1 dimerizes with pro-apoptotic proteins, such as BAK or BAX on the mitochondrial membrane and sequesters pro-apoptotic proteins in a similar fashion as other pro-survival molecules, such as BCL-2 or BCL-XL, to prevent MOMP.4

The anti-apoptotic proteins (e.g., BCL-XL, BCL-2, MCL-1) inhibit both the activator BH3-only proteins and the pore-forming effector proteins by mutual sequestration (T’d arrows). The sensitizer BH3-only proteins (e.g., BAD, NOXA) bind to and inhibit the anti-apoptotic proteins also by mutual sequestration.

IMPLICATIONS IN CANCER

  • MCL-1 is upregulated in cancer cells and promotes tumor cell survival.1
  • Overexpression of the anti-apoptotic gene MCL1 is one of the most common aberrations in human cancer, and it is overexpressed in many types of hematologic malignancies where it is associated with high tumor grade and poor survival.1
    • Increasing molecular evidence indicates that MCL-1 maintains viability of tumor cells through inhibition of apoptosis in several hematologic cancers, including MM and AML, as well as some solid tumors.1
  • In MM, overexpression of MCL-1 leads to apoptosis resistance and is associated with shorter patient survival.5,9
  • The gene amplification and protein overexpression of MCL-1 is the cause of resistance to several chemotherapeutic agents.6
  • Direct MCL-1 inhibitors competitively disrupt the protein-protein interaction between MCL-1 and the BH3 motifs of the pro-apoptotic BCL-2 proteins.7
    • Co-inhibition of MCL-1 and BCL-2 could be an effective, synergistic therapeutic approach 4

Oncogenic Expression

Amplification and overexpression of MCL1 have been reported in various human tumors, including hematologic malignancies and solid tumors (e.g., multiple myeloma, acute myeloid leukemia, hepatocellular carcinoma, non-small-cell lung cancer, breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer).6,8

By evaluating the level of MCL-1 expression via flow cytometry in myeloma cells of patients either at diagnosis or relapse in comparison with that of normal plasma cells in the bone marrow, it was shown that about 50% of multiple myeloma (MM) patients at diagnosis and more than 75% of MM patients at the time of relapse overexpressed MCL-1.9

  • The correlation of MCL-1 expression with disease activity was confirmed by the high expression of MCL-1 found in more than 80% of human myeloma cell lines.9
  1. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/802326
  2. Ramsey HE, et al. A Novel MCL-1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia. Cancer Discov. 2018; 8(12):1566–1581.
  3. Belmar J and SW Fesik. Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacol Ther. 2015;145:76–84.
  4. Lim B, et al. Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox. Cancers. 2019;11:1087; doi:10.3390/cancers11081087.
  5. Slomp A, et al. MCL-1 Inhibition Is Highly Effective Against Multiple Myeloma Cells from Poor Prognosis Patients. Blood. 2018;132(Supplement 1):1916.
  6. Xiang W, et al. MCL-1 inhibition in cancer treatment. OncoTargets and Therapy. 2018;11:7301–7314.
  7. Hird AW, et al. Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacology & Therapeutics. 2019;198:59–67.
  8. Zhang X, et al. Targeting anti-apoptotic BCL-2 family proteins for cancer treatment. Future Med. Chem. 2020;12(7):563–565.
  9. Wuillème-Toumi S, et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia. 2005 Jul;19(7):1248-52.
  10. Kale J, et al. BCL-2 family proteins: changing partners in the dance towards death. Cell Death and Differentiation. 2018;25:65–80. (Image)

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