Controlled gene expression requires the exquisite regulation of transcription initiation, pausing, elongation and termination by RNA polymerase II (POLII), as well as coordinated co-transcriptional processing of nascent mRNAs. Subversion of these fundamental molecular processes disrupts gene expression programs and drives tumorigenesis, with haematological malignancies such as acute myeloid leukaemia (AML) and multiple myeloma (MM) exhibiting aberrant gene expression profiles due to the dysfunctional activity of transcriptional regulators such as MYC and mixed-lineage-leukaemia (MLL)-fusion proteins.
Distinct phases of the POLII transcription cycle are controlled by a class of transcriptional-cyclin-dependent kinases (CDKs) including CDK7, 8, 9, 10, 11, 12 and 13. The development of multiple small molecule inhibitors targeting CDKs 7, 9, 12 and 13 has enabled their key roles for the regulation of initiation, pause-release and elongation stages of the POLII transcription cycle to be deciphered, and has also revealed the importance of their activity in AML. MLL-AML cells exhibit exquisite sensitivity to inhibitors of transcriptional CDKs both in vitro and in vivo, highlighting the therapeutic efficacy of targeting fundamental regulators of the core transcriptional machinery.
CDK11 is over-expressed in a range of haematological and solid malignancies, however until recently relatively little was known about the role of CDK11 for transcriptional regulation and cancer cell viability. The discovery of a previous mis-characterized drug (OTS-964) as a potent small-molecule inhibitor of CDK11, as well as our development of novel chemical-genetic-systems of acute CDK11 degradation and inhibition, has revealed that MLL-AML cells are highly sensitive to the disruption of CDK11 activity. Rapid CDK11 inhibition or degradation potently induces cell cycle arrest and apoptosis of MLL-AML cells. Furthermore, the therapeutic efficacy of anti-CDK11 strategies appears to be connected to the disruption of cancer cell gene expression programs and POLII transcriptional activity. Consequently, these studies highlight CDK11 as a novel therapeutic target for AML treatment.