Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is the most common adult acute leukemia. Survival remains poor, despite decades of scientific advances. Cytotoxic induction chemotherapy regimens are standard-of-care for most patients. Many investigations have highlighted the genomic heterogeneity of AML, and several new targeted therapeutic options have recently been approved. Additional novel therapies are showing promising clinical results and may rapidly transform the therapeutic landscape of AML. Despite the emerging clinical success of B-cell lymphoma (BCL)-2 targeting in AML and a large body of preclinical data supporting myeloid leukemia cell (MCL)-1 as an attractive therapeutic target for AML, MCL-1 targeting remains relatively unexplored, although novel MCL-1 inhibitors are under clinical investigation. Inhibitors of cyclin-dependent kinases (CDKs) involved in the regulation of transcription, CDK9 in particular, are being investigated in AML as a strategy to target MCL-1 indirectly. In this article, we review the basis for CDK inhibition in oncology with a focus on relevant preclinical mechanism-of-action studies of CDK9 inhibitors in the context of their therapeutic potential specifically in AML.

Keywords: BCL-2; CDK; CDK9; MCL-1; acute myeloid leukemia; transcriptional inhibition.

Figure 1

Apoptosis activation in normal and tumor cells. Apoptosis signaling is normally triggered by multiple death signals. There is a finely tuned balance between proapoptotic and antiapoptotic proteins that results in efficient apoptosis induction. MCL-1 and other antiapoptotic proteins block apoptotic effectors like BAK on the surface of the mitochondria. BH3-only proteins, such as NOXA, untether BAK from MCL-1, permitting BAK to cause events that result in cell death.

Figure 2

CDK9 and CDK7 work sequentially to produce mature transcripts. CDK9 is the catalytic subunit of the P-TEFb complex, which is essential in generating mature transcripts. (A) CDK7 phosphorylates the fifth serine on the carboxyl-terminal domain of RNA Pol II, thereby activating RNA Pol II to begin transcribing RNA^a. (B) CDK9 then phosphorylates the second carboxyl-terminal serine to enable elongation of RNA transcripts (113)^a. (C) Inhibition of CDK9 reduces MCL-1 expression (8). ^aReprinted from Morales and Giordano (113), with permission from Taylor & Francis. Brd4, bromodomain-containing protein 4; CDK, cyclin-dependent kinase; MCL-1, myeloid cell leukemia-1; P-TEFb, positive transcription elongation factor b; RNA Pol II, RNA polymerase II.