CDK9 regulation of MCL-1 inhibits apoptosis , enabling 1-5
AML BLAST SURVIVAL
CDK9
MCL-1 mRNA
MCL-1 dependence may drive progression of AML 3 , 6
Disease progression and treatment resistance in a subset of acute myeloid leukemia ( AML ) have been associated with a key anti-apoptotic protein , myeloid cell leukemia 1 ( MCL-1 ). 3 , 6 MCL-1 is a member of the apoptosisregulating BCL-2 family of proteins . 7
In MCL-1 – dependent AML ,* the AML blasts depend primarily on the function of MCL-1 for the antiapoptotic mechanism of survival . 8 , 9 MCL-1 inhibits apoptosis and sustains the survival of AML blasts , allowing them to proliferate , which may lead to relapse . 3 MCL-1 dependence is also associated with resistance to agents that otherwise have activity against leukemic blasts . 7
CDK9 is a key regulator of MCL-1 function 1 , 2 , 5
MCL-1 mRNA transcription in AML blasts is regulated by cyclindependent kinase 9 ( CDK9 ), 1 , 2 a protein that plays a critical role in transcription regulation without directly affecting cell-cycle control . 5 , 10
CDK9-mediated transcriptional regulation of anti-apoptotic proteins , including MCL-1 , is critical for the survival of MCL-1 – dependent AML blasts . 5
Inhibition of CDK9 as a rational therapeutic strategy in MCL-1 – dependent AML 1 , 5 , 7
Because MCL-1 has a short half-life of 2-4 hours , the effects of targeting its upstream regulators are expected to reduce MCL-1 levels rapidly . 11 CDK9 inhibition has been shown to block MCL-1 transcription , resulting in rapid depletion of MCL-1 protein , which may restore apoptosis in MCL-1 – dependent AML blasts . 1 , 5 , 7
Understanding the role of CDK9 in regulating MCL-1 may inform therapeutic targeting strategies in AML .
* The prevalence of MCL-1 – dependent AML is under investigation . booth
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References : 1 . Chen R , Keating MJ , Gandhi V , Plunkett W . Transcription inhibition by flavopiridol : 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 haploinsufficiency 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 – specific STAT5 activation . Blood . 2009 ; 114 ( 24 ): 5034-5043 . 9 . 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 . 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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