The propagation of leukemia requires activation of stem cell transcriptional programs that support long term self-renewal. Previously we showed that the stem cell transcription factor ZFX is critically important for propagation of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). We have identified ZFX target genes in mouse and human leukemia cells using gene expression profiling in conjunction with chromatin immunoprecipitation and massively parallel sequencing (ChIP-seq). Some ZFX target genes have a well established role in controlling mitochondrial function and cell metabolism, suggesting that ZFX is required, in part, to maintain metabolic homeostasis in leukemia propagating cells. The biological functions of other ZFX target genes have not been well characterized. One such gene, FAM92A1, is heavily dependent on ZFX for its expression in mouse and human AML cells. Genetic deletion of ZFX in mouse AML and lentiviral RNAi mediated knockdown of ZFX in human AML cell lines markedly decreased FAM92A1 expression. ChIP-seq showed a ZFX binding site in a dense CpG island between the first and second exons, which was confirmed by ChIP-PCR and suggests that ZFX directly controls FAM92A1 transcription at the proximal promoter. Our studies in sorted murine AML cells and human AML patient samples demonstrate that FAM92A1 is preferentially expressed in the leukemia initiating cell-enriched fractions. Analysis of large-scale gene expression studies of human AML patients revealed that high FAM92A1 expression is associated with the Flt3-ITD mutation, high-risk cytogenetics, early AML recurrence, and patient death. Multivariable analysis showed that it was an independent risk factor for shortened progression-free survival. In addition, FAM92A1 expression is increased in patients with myodysplastic syndrome-refractory anemia with excess blasts. These findings identify FAM92A1 as a marker for ZFX transcriptional activity and AML aggressiveness. The increased expression of FAM92A1 in AML with Flt3-ITD and high-risk cytogenetics suggests that it may be a functionally important component of the ZFX-driven self-renewal transcriptional program in high-risk AML. Definitive functional studies are warranted to establish the role of FAM92A1 in AML propagation.