An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance

Zuber, J., Rappaport, A. R., Luo, W., Wang, E., Chen, C., Vaseva, A. V., Shi, J., Weissmueller, S., Fellman, C., Taylor, M. J., Weissenboeck, M., Graeber, T. G., Kogan, S. C., Vakoc, C. R., Lowe, S. W. (August 2011) An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. Genes & Development, 25 (15). pp. 1628-1640. ISSN 0890-9369

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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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function diseases & disorders > cancer > cancer types > leukemia diseases & disorders > cancer > cancer types
CSHL Authors:	Chen, Chong Fellmann, Christof Lowe, Scott W. Luo, Weijun Rappaport, Amy R. Shi, Junwei Taylor, Meredith J. Vakoc, Christopher R. Vaseva, Angelina V. Weissmueller, Susann Zuber, Johannes
Communities:	CSHL Cancer Center Program > Cancer Genetics CSHL Cancer Center Program > Gene Regulation and Cell Proliferation CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL Cancer Center Shared Resources > DNA Sequencing Service CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Microarray Service CSHL Cancer Center Shared Resources > Microscopy Service CSHL Post Doctoral Fellows CSHL labs > Lowe lab CSHL labs > Vakoc lab School of Biological Sciences > Publications CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User:	CSHL Librarian
Date:	1 August 2011
Date Deposited:	19 Mar 2012 18:57
Last Modified:	30 Oct 2015 20:45
PMCID:	PMC3182026
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/25400

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