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.