Cancer Biology

New Understanding of Leukemia Protein

In an April 30th Nature Cell Biology article, Dr. Joseph Opferman, Ph.D. describes a newfound form of the protein MCL-1. It was previously thought that MCL-1 had only one form and, therefore, only one function. But Dr. Opferman's discovery of another form of the MCL-1 protein may explain why treating leukemia is so challenging.




 MCL-1 is a member of the BCL-2 family of proteins, which are known to help regulate hematopoetic stem cell (HSC) numbers. This is done either by promoting the accumuluation of HSCs, or by destroying them via apoptosis. Members of the BCL-2 family that promote apoptosis have a BH3 domain that, when bound, activates the effector proteins BAX and BAK. These proteins begin the cell death signaling pathway that operates through the mitochondria and the endoplasmic reticulum. On the other hand, members of the BCL-2 pathway that promote HSC survival function as competitive inhibitors. They bind the BH3 domain in order to block the death signaling proteins from binding and beginning the signal transduction pathway that leads to programmed cell death. The MCL-1 protein found to be overly-expressed in cancers is one of the BCL-2 members that promotes the survival of HSCs.

MCL-1 is different than other anti-apoptotic BCL-2 proteins. MCL-1 is necessary for embryonic development, as well as for the survival of many adult cells, including HSCs. Therefore, MCL-1 can replenish red and white blood cells that are lost in the adult or in those undergoing radiation and chemotherapies. That also means that MCL-1 promotes white blood cell survival in leukemia patients, which results in chemotherapy-resistance and relapse.

Dr. Opferman provides a new insight into the MCL-1-mediated cell survival mechanism. Originally, MCL-1 was thought to bind the outer surface of the mitochondrial membrance and inhibit BAX and BAK activity. However, recent evidence suggests that another version of MCL-1 exists. This version is 2K smaller than the original and functions within the inner mitochondrial membrane. The smaller MCL-1 protein helps maintain the inner mitochondrial membrane (IMM), which is essential for energy production. Dr. Opferman performed MCL-1 gene knockout experiments and found that without the IMM MCL-1 protein, the mitochondria were malformed. The fluorescence image to the right shows mitochondrial fusion at three timepoints. MCL-1 is synonymous with both forms of the MCL-1 protein. MCL-1(OM) is the larger, outer membrane form, while MCL-1(Matrix) is the smaller IMM form. It is clear that without the IMM or matrix MCL-1 form, the mitochondria are mishapen. This is important because "mitochondrial fusion is required for cell growth, efficient oxidative phosphorylation and ATP production". In fact, Dr. Opferman found that without the IMM MCL-1 protein, normal mitochondrial bioenergetics were lost. He also found that MCL-1 is necessary for the assembly of F1F0 ATP Synthase oligomers. The gel below indicates less oligomers for both OM and IMM MCL-1 knockouts.

This matrix version of MCL-1 will likely be the target of new drug therapies. If scientists are able to block the smaller form from entering the mitochondria, cells that depend on MCL-1-mediated survival will no longer be able to proliferate. This includes the white blood cells of leukemia patients.

That being said, there are some problems to blocking the matrix version of MCL-1 from entering the mitochondria. This would also prevent normal, healthy blood cells from proliferating as well as hematopoetic stem cells from differentiating into new blood cells. As we obviously need blood cells to survive, there would need to be a way to differentiate between cancerous and normal cells. Either that, or transfusions of normal blood cells would need to be administered along with the MCL-1-targeted therapy.

Sources:

(2012). Key protein's newly discovered form and function may provide novel cancer treatment target. St. Jude Children's Research Hospital, Retrieved from http://www.stjude.org/stjude/v/index.jsp?vgnextoid=afb2dbbd274f6310VgnVCM100000290115acRCRD&rss=medicalscience

(2005). Mcl-1, which can prevent leukemia cell death, is necessary for bone marrow stem cell survival. Cancer, Biology, and Therapy, 4(3), 260. Retrieved from http://www.landesbioscience.com/journals/5/article/1636/

Opferman, J. (2012). Anti-apoptotic mcl-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nature Cell Biology