title: An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance.
abstract: Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations-a phenomenon dubbed "oncogene addiction." Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9-a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Amy R
authors.initials: AR
authors.lastname: Rappaport
authors.forename: Weijun
authors.initials: W
authors.lastname: Luo
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.forename: Angelina V
authors.initials: AV
authors.lastname: Vaseva
authors.forename: Junwei
authors.initials: J
authors.lastname: Shi
authors.forename: Susann
authors.initials: S
authors.lastname: Weissmueller
authors.forename: Christof
authors.initials: C
authors.lastname: Fellmann
authors.forename: Christof
authors.initials: C
authors.lastname: Fellman
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Taylor
authors.forename: Martina
authors.initials: M
authors.lastname: Weissenboeck
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D020570:Genes, myb / Q000235:genetics; D006410:Hematopoiesis; D007938:Leukemia / Q000503:physiopathology*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D020598:Proto-Oncogene Proteins c-myb