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Subtype-specific leukemia oncogenes drive aberrant gene expression profiles that converge on common essential mediators to ensure leukemia self-renewal and inhibition of differentiation. The transcription factor c-MYB functions as one such mediator in a diverse range of leukemias. Here we show for the first time that transcriptional repression of myeloid differentiation associated c-MYB target genes in AML is enforced by the AAA+ ATPase RUVBL2. Silencing RUVBL2 expression resulted in increased binding of c-MYB to these loci and their transcriptional activation. RUVBL2 inhibition resulted in AML cell apoptosis and severely impaired disease progression of established AML in engrafted mice. In contrast, such inhibition had little impact on normal hematopoietic progenitor differentiation. These data demonstrate that RUVBL2 is essential for the oncogenic function of c-MYB in AML by governing inhibition of myeloid differentiation. They also indicate that targeting the control of c-MYB function by RUVBL2 is a promising approach to developing future anti-AML therapies.

HMGA2 promotes lung cancer progression in mice and humans; in mouse and human lung cancer cells, HMGA2 competes with mRNAs like TGFBR3 for the let-7 microRNA family, and in human non-small-cell lung cancer tissue, expression levels of HMGA2 and TGFBR3 are correlated, suggesting that HMGA2 functions both as a protein-coding gene and as a non-coding RNA. Dual mechanism of HMGA2 oncoprotein The Hmga2 gene is often overexpressed in lung cancer, promoting tumorigenesis and metastasis. In a mouse lung tumour model, Julian Downward and colleagues show that Hmga2 functions not only through its protein-coding function, but also by acting as a 'sponge' (or competing endogenous) RNA. By competing with other messenger RNAs for binding to the let-7 microRNA family, Hmga2 regulates, for example, the expression of the TGF-β co-receptor TGFBR3 to promote lung cancer progression. In human non-small-cell lung cancer tissue, the expression levels of HMGA2 and TGFBR3 are correlated, suggesting that HMGA2 also exerts this dual function in patients. Non-small-cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide 1 . As the majority of patients present with invasive, metastatic disease 2 , it is vital to understand the basis for lung cancer progression. Hmga2 is highly expressed in metastatic lung adenocarcinoma, in which it contributes to cancer progression and metastasis 3 , 4 , 5 , 6 . Here we show that Hmga2 promotes lung cancer progression in mouse and human cells by operating as a competing endogenous RNA (ceRNA) 7 , 8 , 9 , 10 , 11 for the let-7 microRNA (miRNA) family. Hmga2 can promote the transformation of lung cancer cells independent of protein-coding function but dependent upon the presence of let-7 sites; this occurs without changes in the levels of let-7 isoforms, suggesting that Hmga2 affects let-7 activity by altering miRNA targeting. These effects are also observed in vivo , where Hmga2 ceRNA activity drives lung cancer growth, invasion and dissemination. Integrated analysis of miRNA target prediction algorithms and metastatic lung cancer gene expression data reveals the TGF-β co-receptor Tgfbr3 (ref. 12 ) as a putative target of Hmga2 ceRNA function. Tgfbr3 expression is regulated by the Hmga2 ceRNA through differential recruitment to Argonaute 2 (Ago2), and TGF-β signalling driven by Tgfbr3 is important for Hmga2 to promote lung cancer progression. Finally, analysis of NSCLC-patient gene-expression data reveals that HMGA2 and TGFBR3 are coordinately regulated in NSCLC-patient material, a vital corollary to ceRNA function. Taken together, these results suggest that Hmga2 promotes lung carcinogenesis both as a protein-coding gene and as a non-coding RNA; such dual-function regulation of gene-expression networks reflects a novel means by which oncogenes promote disease progression.

In this Letter, we reported that Hmga2 promotes lung cancer progression in mouse and human cells by operating as a competing endogenous RNA for the let-7 microRNA family. It has been brought to our attention that the cell lines used in the RNA sequencing (RNA-seq) experiment presented in Extended Data Fig.

Acute myeloid leukaemia (AML) is a disease characterized by the clonal expansion of immature white blood cells, which show increased proliferation, self-renewal and a block of differentiation. Despite recent advances in therapy, AML still causes over half of all leukaemia related paediatric deaths, as cytogenetically defined subgroups with poor prognosis are still prevalent. Chromosomal translocations, which encode abnormal fusion proteins, are common in patients with AML, and the MLL (Mixed Lineage Leukaemia) locus is the most frequently rearranged in paediatric AML. Previous studies in our laboratory used global gene expression analysis in conditionally immortalized MLL-rearranged mouse myeloid cells to demonstrate that Reptin was positively regulated by MLL-fusion genes. Reptin (also known as RUVBL2 or Tip48), functions as part of multi-protein complexes involved in chromatin remodelling, DNA repair, regulation of transcription and ribonucleoprotein assembly. Further work in our laboratory found Reptin to be essential for sustaining the hyperproliferative state and clonogenic potential, as well as suppressing apoptosis, of human AML cells, both MLL-rearranged and non-MLL rearranged. The aim of this study was to investigate the transcriptional pathways regulated by Reptin in human AML and to establish the efficacy of targeting Reptin in vivo. By using an inducible shRNA model to deplete Reptin expression we demonstrate that Reptin is essential for leukaemic progression in vivo, as Reptin knockdown in established human leukaemias resulted in increased survival and the cure of most xenotransplanted mice. Moreover, our analyses of global gene expression data in cells depleted for Reptin expression at different time points indicated that Reptin depletion is negatively correlated with the Leukaemic Stem Cell self-renewal signature. Furthermore, our gene expression results also indicated that Reptin modulates the expression signature of the transcription factors c-MYC and c-MYB, master regulators of survival and self-renewal pathways in AML. Additionally, immunoprecipitation assays identified a novel interaction between endogenous Reptin and c-MYB, and ChIP assays showed decreased binding of c-MYB and the epigenetic mark H3K27ac at the promoter region of the c-MYB target gene MPO after Reptin loss. Collectively, our data identify a new pathway modulated by Reptin and confirm that Reptin is a good therapeutic target for the treatment of AML.