CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo

MYC dysregulation confers a poor prognosis to diffuse large B-cell lymphoma (DLBCL), and effective therapeutic strategies are lacking in relapsed/refractory DLBCL, Burkitt lymphoma and intermediate forms.1, 2 As a master transcriptional regulator, MYC recruits transcription complexes containing RNA polymerase II (Pol II) to facilitate effective transcriptional elongation of MYC gene targets.3 Pol II is fully activated by phosphorylation of a critical serine residue at position 2 within heptapeptide repeats in the carboxy-terminal domain (CTD), a function performed by the positive transcription elongation factor b (P-TEFb; comprising CDK9 and cyclin T1).4 It has been shown that MYC binds and recruits P-TEFb to its targets as a means to activate Pol II.3, 5, 6 More recently, CDK9-mediated transcriptional elongation was reported as essential for tumor maintenance in a genetically defined MYC-driven model of hepatocellular carcinoma.7 Thus, CDK9 dependence may represent a druggable vulnerability in lymphomas with dysregulated MYC expression.