References
Query Results -- Details
MGI Accession ID: MGI:3772373
J Number: J:130798
Other Accession IDs:
Title: BCL-2 and mutant NRAS interact physically and functionally in a mouse model of progressive myelodysplasia.
Authors: Omidvar N; Kogan S; Beurlet S; le Pogam C; Janin A; West R; Noguera ME; Reboul M; Soulie A; Leboeuf C; Setterblad N; Felsher D; Lagasse E; Mohamedali A; Thomas NS; Fenaux P; Fontenay M; Pla M; Mufti GJ; Weissman I; Chomienne C; Padua RA
Journal: Cancer Res
Volume: 67
Issue: 24
Date: 2007 Dec 15
Year: 2007
Pages: 11657-67
Review Status: Peer Reviewed
Abstract:
Myelodysplastic syndromes (MDS) are clonal stem cell hematologic disorders that evolve to acute myeloid leukemia (AML) and thus model multistep leukemogenesis. Activating RAS mutations and overexpression of BCL-2 are prognostic features of MDS/AML transformation. Using NRASD12 and BCL-2, we created two distinct models of MDS and AML, where human (h)BCL-2 is conditionally or constitutively expressed. Our novel transplantable in vivo models show that expression of hBCL-2 in a primitive compartment by mouse mammary tumor virus-long terminal repeat results in a disease resembling human MDS, whereas the myeloid MRP8 promoter induces a disease with characteristics of human AML. Expanded leukemic stem cell (Lin(-)/Sca-1(+)/c-Kit(+)) populations and hBCL-2 in the increased RAS-GTP complex within the expanded Sca-1(+) compartment are described in both MDS/AML-like diseases. Furthermore, the oncogenic compartmentalizations provide the proapoptotic versus antiapoptotic mechanisms, by activating extracellular signal-regulated kinase and AKT signaling, in determination of the neoplastic phenotype. When hBCL-2 is switched off with doxycycline in the MDS mice, partial reversal of the phenotype was observed with persistence of bone marrow blasts and tissue infiltration as RAS recruits endogenous mouse (m)BCL-2 to remain active, thus demonstrating the role of the complex in the disease. This represents the first in vivo progression model of MDS/AML dependent on the formation of a BCL-2:RAS-GTP complex. The colocalization of BCL-2 and RAS in the bone marrow of MDS/AML patients offers targeting either oncogene as a therapeutic strategy.
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