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

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 24; pp. 11657 - 11667
• Main Authors: OMIDVAR, Nader, KOGAN, Scott, SETTERBLAD, Niclas, FELSHER, Dean, LAGASSE, Eric, MOHAMEDALI, Azim, THOMAS, N. Shaun B, FENAUX, Pierre, FONTENAY, Michaela, PLA, Marika, MUFTI, Ghulam J, WEISSMAN, Irving, BEURLET, Stephanie, CHOMIENNE, Christine, PADUA, Rose Ann, LE POGAM, Carole, JANIN, Anne, WEST, Robert, NOGUERA, Maria-Elena, REBOUL, Murielle, SOULIE, Annie, LEBOEUF, Christophe
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.12.2007
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Bone Marrow Transplantation; Cell Transplantation; Colony-Forming Units Assay; Disease Models, Animal; Disease Progression; Genes, bcl-2; Genes, ras; Hematologic and hematopoietic diseases; Immunophenotyping; Leukemia - genetics; Leukemia, Myeloid - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Transgenic; Microscopy, Confocal; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Myelodysplastic Syndromes - physiopathology; Pharmacology. Drug treatments; Spleen; Tumors; Animal model; Vertebrata; Mammalia; n ras Gene; Mouse; C-Onc gene; Rodentia; Malignant hemopathy; Mutation; Protooncogene; Myelodysplastic syndrome; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-0196

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.