Cancer Institute A national cancer institute
designated cancer center

Dean W. Felsher

Publication Details

  • BCL-2 and mutant NRAS interact physically and functionally in a mouse model of progressive myelodysplasia CANCER RESEARCH Omidvar, N., Kogan, S., Beurlet, S., Pogam, C. I., Janin, A., West, R., Noguera, M., Reboul, M., Soulie, A., Leboeuf, C., Setterblad, N., Felsher, D., Lagasse, E., Mohamedali, A., Thomas, N. S., Fenaux, P., Fontenay, M., Pla, M., Mufti, G. J., Weissman, I., Chomienne, C., Padua, R. A. 2007; 67 (24): 11657-11667

    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.

    View details for DOI 10.1158/0008-5472.CAN-07-0196

    View details for Web of Science ID 000251857900025

    View details for PubMedID 18089795

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