Our Research

Understanding AML blast survival through MCL-1 and CDK9 activity

In this emerging, target-driven era of AML treatment, understanding the distinguishing characteristics of AML subsets may be a clinical necessity.1

Emerging research suggests dysregulated levels of myeloid cell leukemia 1 (MCL-1) promote AML blast survival and treatment resistance in a subset* of AML known as MCL-1–dependent AML.2 Preclinical data have shown that MCL-1 can be downregulated with cyclin-dependent kinase 9 (CDK9) inhibition.3,4

MCL-1 is a key anti-apoptotic member of the BCL-2 family of proteins.5

Cyclin-dependent kinases, or CDKs, are a family of proteins that form complexes involved in either cell cycle progression or transcription regulation.9 CDK9 is a transcription-regulating CDK that promotes the expression of MCL-1 by phosphorylating the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II, allowing transcriptional elongation of MCL-1 mRNA.4,10

Preliminary clinical data suggests that CDK9 inhibition may have selective activity against AML blasts, possibly due to dependence on MCL-1. Therefore, MCL-1 regulation via inhibition of CDK9 may be a rational therapeutic strategy for AML.3,4

*The prevalence of MCL-1–dependent AML is being investigated.

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  2. Cassier PA, Castets M, Belhabri A, Vey N. Targeting apoptosis in acute myeloid leukaemia. Br J Cancer. 2017;117(8):1089-1098. doi: 10.1038/bjc,2017.281.
  3. Yin T, Lallena MJ, Kreklau EL, et al. A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol Cancer Ther. 2014;13(6):1442-1456. doi: 10.1158/1535-7163.MCT-13-0849.
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  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. doi: 10.1182/blood-2008-12-196055.
  9. Sonawane YA, Taylor MA, Napolean JV, Rana S, Conteras JI, Natarajan A. Cyclin dependent kinase 9 inhibitors for cancer therapy. J Med Chem. 2016;59(19):8667-8684.
  10. 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.