Requirement for CDK6 in MLL-rearranged acute myeloid leukemia

Theresa Placke, Katrin Faber, Atsushi Nonami, Sarah L. Putwain, Helmut R. Salih, Florian H. Heidel, Alwin Krämer, David E. Root, David A. Barbie, Andrei V. Krivtsov, Scott A. Armstrong, William C. Hahn, Brian J. Huntly, Stephen M. Sykes, Michael D. Milsom, Claudia Scholl, Stefan Fröhling

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

Abstract

Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusionmediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated.We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effectsof loweringCDK6expressionarecloselyphenocopiedbya small-moleculeCDK6inhibitor currently in clinicaldevelopment.These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts.

Original languageEnglish
Pages (from-to)13-23
Number of pages11
JournalBlood
Volume124
Issue number1
DOIs
Publication statusPublished - Jul 3 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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