Requirement for CDK6 in MLL-rearranged acute myeloid leukemia.
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 fusion-mediated 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 effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. 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.
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; German Consortium for Translational Cancer Research, Heidelberg, Germany;
Theresa
T
Placke
Department of Internal Medicine III, Ulm University, Ulm, Germany;
Katrin
K
Faber
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
Atsushi
A
Nonami
Department of Haematology, Cambridge Institute of Medical Research, and Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom;
Sarah L
SL
Putwain
German Consortium for Translational Cancer Research, Heidelberg, Germany; Department of Hematology and Oncology, Eberhard Karls University, Tübingen, Germany;
Helmut R
HR
Salih
Department of Hematology and Oncology, Otto von Guericke University, Magdeburg, Germany;
Florian H
FH
Heidel
German Consortium for Translational Cancer Research, Heidelberg, Germany; Clinical Cooperation Unit Molecular Hematology and Oncology, German Cancer Research Center, and Department of Internal Medicine V, Ruprecht Karls University, Heidelberg, Germany;
Alwin
A
Krämer
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA;
David E
DE
Root
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA;
David A
DA
Barbie
Leukemia Center, Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY;
Andrei V
AV
Krivtsov
Leukemia Center, Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY;
Scott A
SA
Armstrong
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA;
William C
WC
Hahn
Department of Haematology, Cambridge Institute of Medical Research, and Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom;
Brian J
BJ
Huntly
Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA; and.
Stephen M
SM
Sykes
Heidelberg Institute for Stem Cell Technology and Experimental Medicine and Division of Stem Cells and Cancer, Experimental Hematology Group, German Cancer Research Center, Heidelberg, Germany.
Michael D
MD
Milsom
Department of Internal Medicine III, Ulm University, Ulm, Germany;
Claudia
C
Scholl
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; German Consortium for Translational Cancer Research, Heidelberg, Germany;
Stefan
S
Fröhling
D000818:Animals; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic
D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; D051361:Cyclin-Dependent Kinase 6