title: BCL-2 and mutant NRAS interact physically and functionally in a mouse model of progressive myelodysplasia.
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.
authors: 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, Paris, France.
authors: Nader
authors: N
authors: Omidvar
authors: Scott
authors: S
authors: Kogan
authors: Stephanie
authors: S
authors: Beurlet
authors: Carole
authors: C
authors: le Pogam
authors: Anne
authors: A
authors: Janin
authors: Robert
authors: R
authors: West
authors: Maria-Elena
authors: ME
authors: Noguera
authors: Murielle
authors: M
authors: Reboul
authors: Annie
authors: A
authors: Soulie
authors: Christophe
authors: C
authors: Leboeuf
authors: Niclas
authors: N
authors: Setterblad
authors: Dean
authors: D
authors: Felsher
authors: Eric
authors: E
authors: Lagasse
authors: Azim
authors: A
authors: Mohamedali
authors: N Shaun B
authors: NS
authors: Thomas
authors: Pierre
authors: P
authors: Fenaux
authors: Michaela
authors: M
authors: Fontenay
authors: Marika
authors: M
authors: Pla
authors: Ghulam J
authors: GJ
authors: Mufti
authors: Irving
authors: I
authors: Weissman
authors: Christine
authors: C
authors: Chomienne
authors: Rose Ann
authors: RA
authors: Padua
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D017690:Cell Transplantation; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D018450:Disease Progression; D019254:Genes, bcl-2; D011905:Genes, ras; D016130:Immunophenotyping; D007938:Leukemia / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013154:Spleen