Myeloid Cell Leukemia 1 (MCL-1)—Dependent AML
Emerging research suggests that in a subset* of AML, disease progression and treatment resistance may be associated with dependency on a key anti-apoptotic mitochondrial protein, myeloid cell leukemia 1 or MCL-1.1,2
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.3 While AML blasts typically express MCL-1, only a subset of these depend primarily on the function of MCL-1 for the anti-apoptotic mechanism of survival, and this subset is referred to as being MCL-1—dependent.4,5
In MCL-1—dependent AML, MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse.1
Because MCL-1 has a short half-life of approximately 2 to 4 hours, the effects of targeting its upstream regulators are expected to reduce MCL-1 levels rapidly.6
*The prevalence of MCL-1—dependent AML is under investigation.
1. Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120-125. 2. Xiang Z, Luo H, Payton JE, et al. Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia. J Clin Invest. 2010;120(6):2109-2118. 3. Pandey MK, Prasad S, Tyagi AK, et al. Targeting cell survival proteins for cancer cell death. Pharmaceuticals (Basel). 2016;9(1):e11. 4. Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, et al. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood. 2009;114(24):5034-5043. 5. Butterworth M, Pettitt A, Varadarajan S, Cohen GM. BH3 profiling and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells. Br J Cancer. 2016;114(6):638-641. 6. Gores GJ, Kaufmann SH. Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors. Genes Dev. 2012;26(4):305-311.