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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