NRAS G12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia

Abstract

Key Points• NRAS G12V maintains leukemia self-renewal in a genetically engineered murine model of AML.• NRAS G12V differentially regulates transcription and signaling among leukemic subpopulations.Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRAS G12V ). Using computational approaches to explore our gene-expression data sets, we found that NRAS G12V enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9-and Myb-dependent leukemia self-renewal geneexpression program. NRAS G12V was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRAS G12V -mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1 Low cells, which harbor leukemia stem cells, were preferentially sensitive to NRAS G12V withdrawal. NRAS G12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction. (Blood. 2014;124(22):3274-3283)

Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia

“…MLL-fusion proteins aberrantly regulate MLL target genes (such as the Hoxa genes and Meis1) inducing neoplastic transformation by activating inappropriate self-renewal programs in lineage-committed progenitors (Somervaille and Cleary, 2010). The oncogenic self-renewal transcriptional signature triggered by MLL translocations is essential for the establishment and maintenance of the MLL-rearranged LSC pool, and specific pathways controlled by Wnt/b-catenin, Myb, and NRAS have been proposed as important in the control of this LSC-associated program (Sachs et al, 2014;Wang et al, 2010;Zuber et al, 2011). However, a greater understanding of the critical determinants of LSC self-renewal and their clinical relevance is urgently needed to identify better prognostic markers and develop effective therapies for this aggressive type of AML.…”

mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress

“…ML604440, a β1i inhibitor (Basler et al, 2012), did not induce PARP1 cleavage but potentiated the effect of PR957 (Figures 5E and S5D). The RAS mutation-dependent effect of PR957 was further confirmed with MIAPaCa2 pancreatic cancer cells that harbor KRAS G12C mutation (Figure 5G), and mouse primary AML cells expressing NRAS G12V mutant (Sachs et al, 2014) (Figure 5H). In contrast, bortezomib, which inhibits all types of proteasomes, induced apoptosis regardless of TSC1 or RAS mutation (Figures 5I and S5H-J).…”

Reprogramming of serine metabolism is an actionable vulnerability inFLT3-ITDdriven acute myeloid leukaemia

“…The recent approval of the first generation panreceptor tyrosine kinase (RTK) inhibitor midostaurin as frontline therapy for patients with FLT3-ITD mutations has resulted in significant interest in targeting FLT3 in the context of AML (7). Although in AML has been studied (53,54), to the best of our knowledge, the work described herein is the first study to address the importance of FLT3-ITD in the maintenance of MLL-AF9-driven AML.…”