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BCL-2 and Mutant NRAS Interact Physically and Functionally in a Mouse Model of Progressive Myelodysplasia

¹ Institut National de la Sante et de la Recherche Medicale U718 and 728, Université Paris 7 Denis Diderot, Faculté de Médicine, Institut Universitaire d'Hématologie-IFR105, AP-HP, Hôpital Saint-Louis; ² Service d'Hématologie Clinique, Hôpital Avicenne (AP-HP)/Université Paris 13; ³ Département d'Hématologie, Institut Cochin, Hôpital Cochin, Paris, France; Schools of ⁴ Biosciences and ⁵ Medicine, Cardiff University, Cardiff, United Kingdom; ⁶ University of California, San Francisco, California; ⁷ Stanford University, Stanford, California; ⁸ McGowan Institute of Regenerative Medicine, Pittsburgh, Pennsylvania; and ⁹ Department of Haematological Medicine, Guy's, King's and Saint Thomas' School of Medicine, London, United Kingdom

Requests for reprints: Rose Ann Padua, Institut Universitaire d'Hématologie-IFR105, Institut National de la Sante et de la Recherche Medicale UMR-S-718, Laboratoire d'Hématologie Paris, Paris, France. Phone: 33-1-53-72-40-72; Fax: 33-1-53-72-40-16; E-mail: padua{at}stlouis.inserm.fr.

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. [Cancer Res 2007;67(24):11657–67]