title: Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia.
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.
authors.affiliation: 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.
authors.forename: Margherita
authors.initials: M
authors.lastname: Ghisi
authors.affiliation: 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.
authors.forename: Lev
authors.initials: L
authors.lastname: Kats
authors.affiliation: 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.
authors.forename: Frederick
authors.initials: F
authors.lastname: Masson
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kratina
authors.affiliation: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Eva
authors.initials: E
authors.lastname: Vidacs
authors.affiliation: 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.
authors.forename: Omer
authors.initials: O
authors.lastname: Gilan
authors.affiliation: Research Computing Facility, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC, Australia.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Doyle
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Newbold
authors.affiliation: 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.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Bolden
authors.affiliation: 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.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Fairfax
authors.affiliation: 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.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: de Graaf
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Firth
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, 3004 VIC, Australia.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dickins
authors.affiliation: 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.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Corcoran
authors.affiliation: 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.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dawson
authors.affiliation: 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.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: 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.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D009374:Neoplasms, Experimental; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D016019:Survival Analysis; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051788:Myeloid-Lymphoid Leukemia Protein