Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice

Parikh, Chaitali; Subrahmanyam, Ramesh; Ren, Ruibao

doi:10.1182/blood-2004-08-009498

Cited by 82 publications

(67 citation statements)

References 32 publications

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“…39 These disease phenotypes were also different from the development of MPD in the earlier reports. 39,40 This discrepancy might be due to the differences in the experimental systems, such as the retroviral transduction and mice strains. Meanwhile, the BM progenitors transduced with Hoxa9 and NRAS G12V seemed to result in engraftment failure under sublethal conditioning, but these rapidly developed myeloid malignancy under lethal conditioning.…”

Section: Discussionmentioning

confidence: 99%

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

et al. 2009

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Mixed-lineage-leukemia (MLL) fusion oncogenes are closely involved in infant acute leukemia, which is frequently accompanied by mutations or overexpression of FMS-like receptor tyrosine kinase 3 (FLT3). Earlier studies have shown that MLL fusion proteins induced acute leukemia together with another mutation, such as an FLT3 mutant, in mouse models. However, little has hitherto been elucidated regarding the molecular mechanism of the cooperativity in leukemogenesis. Using murine model systems of the MLL-fusion-mediated leukemogenesis leading to oncogenic transformation in vitro and acute leukemia in vivo, this study characterized the molecular network in the cooperative leukemogenesis. This research revealed that MLL fusion proteins cooperated with activation of Ras in vivo, which was substitutable for Raf in vitro, synergistically, but not with activation of signal transducer and activator of transcription 5 (STAT5), to induce acute leukemia in vivo as well as oncogenic transformation in vitro. Furthermore, Hoxa9, one of the MLL-targeted critical molecules, and activation of Ras in vivo, which was replaceable with Raf in vitro, were identified as fundamental components sufficient for mimicking MLL-fusion-mediated leukemogenesis. These findings suggest that the molecular crosstalk between aberrant expression of Hox molecule(s) and activated Raf may have a key role in the MLL-fusion-mediated-leukemogenesis, and may thus help develop the novel molecularly targeted therapy against MLL-related leukemia.

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Section: Discussionmentioning

confidence: 99%

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

et al. 2009

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“…In murine models, oncogenic NRAS has not only produced chronic myelogenous leukemia and acute myelogenous leukemia-like diseases, but also increased mast cells in the blood, bone marrow, liver and spleen, a phenotype consistent with aggressive systemic mastocytosis. [3][4] In this study, we demonstrate that RAS gene expression increases with mast cell maturation and that activating mutations, specifically in NRAS, are found exclusively in advanced forms of systemic mastocytosis and may precede the KIT-D816V mutation in clonal development.…”

Section: Introductionmentioning

confidence: 96%

Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis

Wilson¹,

Marić²,

Šimáková³

et al. 2010

Haematologica

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Cooperating genetic events are likely to contribute to the phenotypic diversity of KIT-D816V systemic mastocytosis. In this study, 44 patients with KIT-D816V systemic mastocytosis were evaluated for coexisting NRAS, KRAS, HRAS or MRAS mutations. Activating NRAS mutations were identified in 2 of 8 patients with advanced disease. NRAS mutations were not found in patients with indolent systemic mastocytosis. To better understand the clonal evolution of mastocytosis, we evaluated the cell compartments impacted by the NRAS and KIT mutations. Clonal mast cells harbored both mutations. KIT-D816V was not detected in bone marrow CD34 + progenitors, whereas the NRAS mutation was present. These findings suggest that NRAS mutations may have the potential to precede KIT-D816V in clonal development. Unlike other mature lineages, mast cell survival is dependent on KIT and the presence of these two activating mutations may have a greater impact on the expansion of this cell compartment and in resultant disease severity. (Clinicaltrials.gov identifier: NCT00044122, NCT00001756)

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“…Transplanting irradiated recipients with bone marrow cells that were infected with this MSCV-GFP-IRES-Nras G12D vector rapidly caused a CMML-like MPD or AML. 33 Importantly, all of these malignancies harbored clonal murine stem cell leukemia integrations, which infers the need for cooperating mutations in vivo. Taken together, whereas data from transgenic and retroviral transduction/transplantation experiments indicate that oncogenic Nras initiates leukemic growth under some experimental conditions, it has not been possible to distinguish Nras G12D intrinsic phenotypes or to directly assess the functional output of endogenous Nras G12D expression in hematopoietic cells.…”

Section: Nras G12d In Hematopoiesis and Leukemogenesis 2029mentioning

confidence: 99%

Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus

Haigis

McDaniel³

et al. 2011

Blood

135

151

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Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice

Cited by 82 publications

References 32 publications

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis

Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus

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