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CDK9 regulation of MCL-1
inhibits apoptosis, enabling
1-5
AML BLAST
SURVIVAL
CDK9
MCL-1 mRNA
MCL-1 dependence may
3,6
drive progression of AML CDK9 is a key regulator
1,2,5
of MCL-1 Disease progression and treatment MCL-1 mRNA transcription in AML blasts Inhibition of CDK9 as a
rational therapeutic strategy
1,5,7
in MCL-1–dependent AML
resistance in a subset of acute myeloid is regulated by cyclin-dependent kinase leukemia (AML) have been associated 9 (CDK9), 1,2 a protein that plays a critical Because MCL-1 has a short half-life of
with a key anti-apoptotic protein, role in transcription regulation without myeloid cell leukemia 1 (MCL-1). 3,6 directly affecting cell-cycle control. 5,10
upstream regulators are expected to
reduce MCL-1 levels rapidly. 11 CDK9
MCL-1 is a member of the apoptosis-
inhibition has been shown to block
regulating BCL-2 family of proteins. 7
In MCL-1–dependent AML,* the
AML blasts depend primarily on
the function of MCL-1 for the anti-
apoptotic mechanism of survival. 8,9
MCL-1 transcription, resulting in rapid
CDK9-mediated transcriptional
regulation of anti-apoptotic
genes, including MCL-1,
is critical for the survival of
MCL-1–dependent AML blasts.
is also associated with resistance to
restore apoptosis in MCL-1–dependent
Understanding the role of CDK9
the survival of AML blasts, which may
lead to relapse. MCL-1 dependence
depletion of MCL-1 protein, which may
AML blasts. 1,5,7
MCL-1 inhibits apoptosis and sustains
3
2-4 hours, the effects of targeting its
in regulating MCL-1 may inform
5
therapeutic targeting strategies
in AML.
agents that otherwise have activity
against leukemic blasts. 7
*The prevalence of MCL-1–dependent AML
is under investigation.
A matter of cell life
and cell death
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References: 1. Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by fl avopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106(7):2513-2519. 2. Ocana A, Pandiella A. Targeting oncogenic
vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234. 3. 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. 4. Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29. 5. Sonawane YA, Taylor MA,
Napoleon JV, Rana S, Contreras JI, Natarajan A. Cyclin dependent kinase 9 inhibitors for cancer therapy. J Med Chem. 2016;59(19):8667-8684. 6. Xiang Z, Luo H, Payton JE, et al. Mcl1 haploinsuffi ciency protects mice from Myc-induced
acute myeloid leukemia. J Clin Invest. 2010;120(6):2109-2118. 7. Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-
748. 8. 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–specifi c STAT5 activation. Blood. 2009;114(24):5034-5043. 9.
Butterworth M, Pettitt A, Varadarajan S, Cohen GM. BH3 profi ling and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells. Br J Cancer. 2016;114(6):638-641. 10. Morales F, Giordano A. Overview of CDK9 as a
target in cancer research. Cell Cycle. 2016;15(4):519-527. 11. 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.
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