BCL-2 and mutant NRAS interact physically and functionally in a mouse model of progressive myelodysplasia.
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.
Omidvar
Nader
N
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.
Kogan
Scott
S
Beurlet
Stephanie
S
le Pogam
Carole
C
Janin
Anne
A
West
Robert
R
Noguera
Maria-Elena
ME
Reboul
Murielle
M
Soulie
Annie
A
Leboeuf
Christophe
C
Setterblad
Niclas
N
Felsher
Dean
D
Lagasse
Eric
E
Mohamedali
Azim
A
Thomas
N Shaun B
NS
Fenaux
Pierre
P
Fontenay
Michaela
M
Pla
Marika
M
Mufti
Ghulam J
GJ
Weissman
Irving
I
Chomienne
Christine
C
Padua
Rose Ann
RA
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