TY - JOUR
T1 - Murine Pten(-/-) T-ALL requires non-redundant PI3K/mTOR and DLL4/Notch1 signals for maintenance and γc/TCR signals for thymic exit
AU - Hagenbeek, Thijs J.
AU - Wu, Xiumin
AU - Choy, Lisa
AU - Sanchez-Irizarry, Cheryll
AU - Seshagiri, Somasekar
AU - Stinson, Jeremy
AU - Siebel, Christian W.
AU - Spits, Hergen
PY - 2014
Y1 - 2014
N2 - T cell acute lymphoblastic leukemias (T-ALLs) commonly display constitutively active PI3K/mTOR and Notch signaling. However, controversy surrounds whether these pathways have independent functions and whether Pten loss is sufficient to generate resistance to Notch inhibition. Here we report that Pten(-/-) T-ALL is sensitive to either PI3K/mTOR or Notch inhibition alone, each pathway controlling distinct downstream signaling events that cannot be rescued by activation of the other pathway, consistent with independent, non-redundant functions. Although many human T-ALLs display constitutively activating Notch1 mutations, primary Pten(-/-) T-ALLs expressed wild-type Notch1 and depended on the Notch ligand DLL4 in vivo. Pten(-/-) T-ALLs with or without γc/TCR signaling responded similarly to PI3K/mTOR and Notch inhibition, although extended culture in vitro occasionally induced Notch-independent growth. However, unlike the T-ALLs lacking only Pten, eight of 23 Pten(-/-) T-ALLs that also lacked γc/TCR signaling accumulated Notch1 mutations, suggesting crosstalk between γc/TCR and Notch signaling. Importantly, we concluded that loss of γc/TCR signaling also inhibited thymic exit of Pten(-/-) T-ALLs. Our results may be clinically relevant in revealing that Pten loss is not sufficient to engender resistance to Notch inhibition, uncovering a role in T-ALL for ligand-dependent induction of wild-type Notch1, and suggesting that γc/TCR signaling could be targeted for preventing metastasis
AB - T cell acute lymphoblastic leukemias (T-ALLs) commonly display constitutively active PI3K/mTOR and Notch signaling. However, controversy surrounds whether these pathways have independent functions and whether Pten loss is sufficient to generate resistance to Notch inhibition. Here we report that Pten(-/-) T-ALL is sensitive to either PI3K/mTOR or Notch inhibition alone, each pathway controlling distinct downstream signaling events that cannot be rescued by activation of the other pathway, consistent with independent, non-redundant functions. Although many human T-ALLs display constitutively activating Notch1 mutations, primary Pten(-/-) T-ALLs expressed wild-type Notch1 and depended on the Notch ligand DLL4 in vivo. Pten(-/-) T-ALLs with or without γc/TCR signaling responded similarly to PI3K/mTOR and Notch inhibition, although extended culture in vitro occasionally induced Notch-independent growth. However, unlike the T-ALLs lacking only Pten, eight of 23 Pten(-/-) T-ALLs that also lacked γc/TCR signaling accumulated Notch1 mutations, suggesting crosstalk between γc/TCR and Notch signaling. Importantly, we concluded that loss of γc/TCR signaling also inhibited thymic exit of Pten(-/-) T-ALLs. Our results may be clinically relevant in revealing that Pten loss is not sufficient to engender resistance to Notch inhibition, uncovering a role in T-ALL for ligand-dependent induction of wild-type Notch1, and suggesting that γc/TCR signaling could be targeted for preventing metastasis
U2 - https://doi.org/10.1016/j.canlet.2013.12.027
DO - https://doi.org/10.1016/j.canlet.2013.12.027
M3 - Article
C2 - 24384093
SN - 0304-3835
VL - 346
SP - 237
EP - 248
JO - Cancer Letters
JF - Cancer Letters
IS - 2
ER -