Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia

Margherita Ghisi; Lev Kats; Frederick Masson; Jason Li; Tobias Kratina; Eva Vidacs; Omer Gilan; Maria A Doyle; Andrea Newbold; Jessica E Bolden; Kirsten A Fairfax; Carolyn A de Graaf; Matthew Firth; Johannes Zuber; Ross A Dickins; Lynn M Corcoran; Mark A Dawson; Gabrielle T Belz; Ricky W Johnstone

doi:10.1016/j.ccell.2016.05.019

Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia

Cancer Cell. 2016 Jul 11;30(1):59-74. doi: 10.1016/j.ccell.2016.05.019. Epub 2016 Jun 30.

Authors

Margherita Ghisi¹, Lev Kats², Frederick Masson³, Jason Li⁴, Tobias Kratina⁵, Eva Vidacs⁶, Omer Gilan², Maria A Doyle⁷, Andrea Newbold², Jessica E Bolden⁸, Kirsten A Fairfax⁸, Carolyn A de Graaf⁸, Matthew Firth⁵, Johannes Zuber⁹, Ross A Dickins¹⁰, Lynn M Corcoran⁵, Mark A Dawson², Gabrielle T Belz⁵, Ricky W Johnstone¹¹

Affiliations

¹ Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, 3004 VIC, Australia. Electronic address: margherita.ghisi@monash.edu.
² Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3010 VIC, Australia.
³ Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, 3084 VIC, Australia; Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010 VIC, Australia.
⁴ The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3010 VIC, Australia; Bioinformatics Core, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
⁵ Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052 VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010 VIC, Australia.
⁶ Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
⁷ Research Computing Facility, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
⁸ Department of Medical Biology, The University of Melbourne, Parkville, 3010 VIC, Australia; Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052 VIC, Australia.
⁹ Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
¹⁰ Australian Centre for Blood Diseases, Monash University, Melbourne, 3004 VIC, Australia.
¹¹ Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3010 VIC, Australia. Electronic address: ricky.johnstone@petermac.org.

PMID: 27374225
DOI: 10.1016/j.ccell.2016.05.019

Abstract

E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8;21) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8;21) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Chromosomes, Human, Pair 21 / genetics
Chromosomes, Human, Pair 8 / genetics
Gene Expression Regulation, Leukemic
Humans
Inhibitor of Differentiation Protein 2 / genetics*
Inhibitor of Differentiation Protein 2 / metabolism
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology*
Mice
Myeloid-Lymphoid Leukemia Protein / genetics*
Myeloid-Lymphoid Leukemia Protein / metabolism
Neoplasms, Experimental
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
Prognosis
Stem Cells / cytology
Stem Cells / metabolism
Survival Analysis
Transcription Factor 7-Like 2 Protein / genetics*
Transcription Factor 7-Like 2 Protein / metabolism
Translocation, Genetic*

Substances

ID2 protein, human
Inhibitor of Differentiation Protein 2
MLL-AF9 fusion protein, human
Oncogene Proteins, Fusion
TCF7L2 protein, human
Transcription Factor 7-Like 2 Protein
Myeloid-Lymphoid Leukemia Protein