PMID- 18089795
OWN - NLM
STAT- MEDLINE
DCOM- 20080115
LR  - 20071219
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 24
DP  - 2007 Dec 15
TI  - BCL-2 and mutant NRAS interact physically and functionally in a mouse model of 
      progressive myelodysplasia.
PG  - 11657-67
AB  - 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.
FAU - Omidvar, Nader
AU  - Omidvar N
AD  - Institut National de la Sante et de la Recherche Medicale U718 and 728, 
      Universite Paris 7 Denis Diderot, Faculte de Medicine, Institut Universitaire 
      d'Hematologie-IFR105, Paris, France.
FAU - Kogan, Scott
AU  - Kogan S
FAU - Beurlet, Stephanie
AU  - Beurlet S
FAU - le Pogam, Carole
AU  - le Pogam C
FAU - Janin, Anne
AU  - Janin A
FAU - West, Robert
AU  - West R
FAU - Noguera, Maria-Elena
AU  - Noguera ME
FAU - Reboul, Murielle
AU  - Reboul M
FAU - Soulie, Annie
AU  - Soulie A
FAU - Leboeuf, Christophe
AU  - Leboeuf C
FAU - Setterblad, Niclas
AU  - Setterblad N
FAU - Felsher, Dean
AU  - Felsher D
FAU - Lagasse, Eric
AU  - Lagasse E
FAU - Mohamedali, Azim
AU  - Mohamedali A
FAU - Thomas, N Shaun B
AU  - Thomas NS
FAU - Fenaux, Pierre
AU  - Fenaux P
FAU - Fontenay, Michaela
AU  - Fontenay M
FAU - Pla, Marika
AU  - Pla M
FAU - Mufti, Ghulam J
AU  - Mufti GJ
FAU - Weissman, Irving
AU  - Weissman I
FAU - Chomienne, Christine
AU  - Chomienne C
FAU - Padua, Rose Ann
AU  - Padua RA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
SB  - IM
MH  - Animals
MH  - Bone Marrow Transplantation
MH  - Cell Transplantation
MH  - Colony-Forming Units Assay
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - *Genes, bcl-2
MH  - *Genes, ras
MH  - Immunophenotyping
MH  - Leukemia/genetics
MH  - Leukemia, Myeloid/genetics
MH  - Mice
MH  - Mice, Transgenic
MH  - Microscopy, Confocal
MH  - Myelodysplastic Syndromes/*genetics/pathology/physiopathology
MH  - Spleen
EDAT- 2007/12/20 09:00
MHDA- 2008/01/16 09:00
CRDT- 2007/12/20 09:00
PHST- 2007/12/20 09:00 [pubmed]
PHST- 2008/01/16 09:00 [medline]
PHST- 2007/12/20 09:00 [entrez]
AID - 67/24/11657 [pii]
AID - 10.1158/0008-5472.CAN-07-0196 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Dec 15;67(24):11657-67. doi: 10.1158/0008-5472.CAN-07-0196.