TY - JOUR
T1 - c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma
AU - Weng, Andrew P.
AU - Millholland, John M.
AU - Yashiro-Ohtani, Yumi
AU - Arcangeli, Marie Laure
AU - Lau, Arthur
AU - Wai, Carol
AU - Del Bianco, Cristina
AU - Rodriguez, Carlos G.
AU - Sai, Hong
AU - Tobias, John
AU - Li, Yueming
AU - Wolfe, Michael S.
AU - Shachaf, Cathy
AU - Felsher, Dean
AU - Blacklow, Stephen C.
AU - Pear, Warren S.
AU - Aster, Jon C.
PY - 2006/8/1
Y1 - 2006/8/1
N2 - Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1-c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells.
AB - Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1-c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells.
KW - Leukemia
KW - Myc
KW - Notch
KW - T cell
KW - Transformation
UR - http://www.scopus.com/inward/record.url?scp=33746546368&partnerID=8YFLogxK
U2 - 10.1101/gad.1450406
DO - 10.1101/gad.1450406
M3 - Article
C2 - 16847353
AN - SCOPUS:33746546368
SN - 0890-9369
VL - 20
SP - 2096
EP - 2109
JO - Genes and Development
JF - Genes and Development
IS - 15
ER -