PMID- 22116551
OWN - NLM
STAT- MEDLINE
DCOM- 20120705
LR  - 20130304
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 26
IP  - 5
DP  - 2012 May
TI  - Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations 
      in T-cell leukemogenesis.
PG  - 1038-45
LID - 10.1038/leu.2011.328 [doi]
AB  - Ras guanyl nucleotide-releasing proteins (RasGRPs) are activators of Ras. 
      Previous studies have indicated the possible involvement of RasGRP1 and RasGRP4 
      in leukemogenesis. Here, the predominant role of RasGRP1 in T-cell leukemogenesis 
      is clarified. Notably, increased expression of RasGRP1, but not RasGRP4, was 
      frequently observed in human T-cell malignancies. In a mouse bone marrow 
      transplantation model, RasGRP1 exclusively induced T-cell acute lymphoblastic 
      leukemia/lymphoma (T-ALL) after a shorter latency when compared with RasGRP4. 
      Accordingly, Ba/F3 cells transduced with RasGRP1 survived longer under growth 
      factor withdrawal or phorbol ester stimulation than those transduced with 
      RasGRP4, presumably due to the efficient activation of Ras. Intriguingly, NOTCH1 
      mutations resulting in a gain of function were found in 77% of the 
      RasGRP1-mediated mouse T-ALL samples. In addition, gain-of-function NOTCH1 
      mutation was found in human T-cell malignancy with elevated expression of 
      RasGRP1. Importantly, RasGRP1 and NOTCH1 signaling cooperated in the progression 
      of T-ALL in the murine model. The leukemogenic advantage of RasGRP1 over RasGRP4 
      was attenuated by the disruption of a protein kinase C phosphorylation site 
      (RasGRP1(Thr184)) not present on RasGRP4. In conclusion, cooperation between 
      aberrant expression of RasGRP1, a strong activator of Ras, and secondary 
      gain-of-function mutations of NOTCH1 have an important role in T-cell 
      leukemogenesis.
FAU - Oki, T
AU  - Oki T
AD  - Division of Cellular Therapy, The Institute of Medical Science, The University of 
      Tokyo, Tokyo, Japan.
FAU - Kitaura, J
AU  - Kitaura J
FAU - Watanabe-Okochi, N
AU  - Watanabe-Okochi N
FAU - Nishimura, K
AU  - Nishimura K
FAU - Maehara, A
AU  - Maehara A
FAU - Uchida, T
AU  - Uchida T
FAU - Komeno, Y
AU  - Komeno Y
FAU - Nakahara, F
AU  - Nakahara F
FAU - Harada, Y
AU  - Harada Y
FAU - Sonoki, T
AU  - Sonoki T
FAU - Harada, H
AU  - Harada H
FAU - Kitamura, T
AU  - Kitamura T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111125
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (DNA Primers)
RN  - 0 (NOTCH1 protein, human)
RN  - 0 (Receptor, Notch1)
RN  - 0 (ras Guanine Nucleotide Exchange Factors)
RN  - EC 2.7.11.13 (Protein Kinase C)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Bone Marrow Transplantation
MH  - Cell Line
MH  - DNA Primers
MH  - Flow Cytometry
MH  - Gene Expression Profiling
MH  - Humans
MH  - Mice
MH  - *Mutation
MH  - Phosphorylation
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/*metabolism/pathology
MH  - Protein Kinase C/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptor, Notch1/genetics/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - ras Guanine Nucleotide Exchange Factors/genetics/*metabolism
EDAT- 2011/11/26 06:00
MHDA- 2012/07/06 06:00
CRDT- 2011/11/26 06:00
PHST- 2011/11/26 06:00 [entrez]
PHST- 2011/11/26 06:00 [pubmed]
PHST- 2012/07/06 06:00 [medline]
AID - leu2011328 [pii]
AID - 10.1038/leu.2011.328 [doi]
PST - ppublish
SO  - Leukemia. 2012 May;26(5):1038-45. doi: 10.1038/leu.2011.328. Epub 2011 Nov 25.