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

Omidvar, Nader, Kogan, S., Beurlet, S., le Pogam, C., Janin, A., West, Robert R., Noguera, M.-E., Reboul, M., Soulie, A., Leboeuf, C., Setterblad, N., Felsher, D., Lagasse, E., Mohamedali, A., Thomas, N. S. B., Fenaux, P., Fontenay, M., Pla, M., Mufti, G. J., Weissman, I., Chomienne, C. and Padua, R. A. 2007. BCL-2 and Mutant NRAS Interact Physically and Functionally in a Mouse Model of Progressive Myelodysplasia. Cancer Research 67 (24) , pp. 11657-11667. 10.1158/0008-5472.CAN-07-0196

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	multistep leukemogenesis; oncogenic NRAS; Animal models of cancer; Leukemias and lymphomas; bcl-2 pathways: anti- and proapoptotic
Publisher:	American Association for Cancer Research
ISSN:	0008-5472
Last Modified:	04 Jun 2017 02:09
URI:	https://orca.cardiff.ac.uk/id/eprint/9877

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