Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia

Hannah McCalmont, Ka Leung Li, Luke Jones, John Toubia, Sarah C. Bray, Debora A. Casolari, Chelsea Mayoh, Saumya E. Samaraweera, Ian D. Lewis, Rab K. Prinjha, Nicholas Smithers, Shudong Wang, Richard B. Lock, Richard J. D'Andrea

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20 Citations (Scopus)

Abstract

Chromosomal rearrangements of the lysine methyltransferase 2A (KMT2A or MLL) gene are observed in ;10% of all acute leukemias, with particularly high frequency (;80%) in infant acute lymphoblastic leukemia (ALL),1 where, despite aggressive chemotherapy, patients still experience poor outcome and long-term side effects.2 Mixed lineage leukemia (MLL) rearrangements (MLL-r) also indicate particularly poor outcomes for patients with acute myeloid leukemia (AML).3 Mechanistically, MLL-r frequently generates fusion proteins involving partners that function in the super elongation complex,4 the result of which is aberrant recruitment to MLL target genes of the positive transcription elongation factor b (PTEFb), composed of cyclin-dependent kinase 9 (CDK9) as the catalytic subunit.5 CDK9 positively regulates transcription elongation through phosphorylation of serine 2 of RNA polymerase II (RNAPII).6 Given the central role of CDK9 in the leukemic MLL-r gene-expression program,7 and the well-described ability of CDK9 inhibitors to reduce levels of the short-lived prosurvival protein MCL1,8 a number of CDK9 inhibitors have been selected for clinical trials focusing on acute leukemias, including those with MLL-r.8,9 In MLL-r leukemia, the bromodomain and extraterminal (BET) family member bromodomain-containing 4 (BRD4)10 acts to recruit PTEFb to superenhancers and together with CDK9 drives increased expression of many oncogenes including MYC.11,12 The roles of CDK9 and BRD4 in MLL-r leukemias present a strong case for testing inhibitors of these proteins in combination as a potential treatment of MLL-r acute leukemias.

Original languageEnglish
Pages (from-to)296-300
Number of pages5
JournalBlood Advances
Volume4
Issue number2
DOIs
Publication statusPublished or Issued - 28 Jan 2020

ASJC Scopus subject areas

  • Hematology

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