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BCL-2 and Mutant NRAS Interact Physically and Functionally in a Mouse Model of Progressive Myelodysplasia
- Source :
- Cancer Research. 67:11657-11667
- Publication Year :
- 2007
- Publisher :
- American Association for Cancer Research (AACR), 2007.
-
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. [Cancer Res 2007;67(24):11657–67]
- Subjects :
- Neuroblastoma RAS viral oncogene homolog
Cancer Research
Myeloid
Cell Transplantation
Mice, Transgenic
Biology
Immunophenotyping
Colony-Forming Units Assay
Mice
hemic and lymphatic diseases
medicine
Animals
Bone Marrow Transplantation
Leukemia
Microscopy, Confocal
Oncogene
Myeloid leukemia
medicine.disease
Genes, bcl-2
Disease Models, Animal
Genes, ras
medicine.anatomical_structure
Oncology
Leukemia, Myeloid
Myelodysplastic Syndromes
Disease Progression
Cancer research
Bone marrow
Stem cell
Spleen
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 67
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....4220ceb7b90c23b39447c210811505ce