TY - JOUR
T1 - Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss
AU - Medyouf, Hind
AU - Gao, Xiuhua
AU - Armstrong, Florence
AU - Gusscott, Samuel
AU - Liu, Qing
AU - Gedman, Amanda Larson
AU - Matherly, Larry H.
AU - Schultz, Kirk R.
AU - Pflumio, Francoise
AU - You, Mingjian James
AU - Weng, Andrew P.
PY - 2010/2/11
Y1 - 2010/2/11
N2 - NOTCH1 is activated by mutation in more than 50% of human T-cell acute lymphoblastic leukemias (T-ALLs) and inhibition of Notch signaling causes cell-cycle/growth arrest, providing rationale for NOTCH1 as a therapeutic target. The tumor suppressor phosphatase and tensin homolog (PTEN) is also mutated or lost in up to 20% of cases. It was recently observed among human T-ALL cell lines that PTEN loss correlated with resistance to Notch inhibition, raising concern that patients with PTEN-negative disease may fail Notch inhibitor therapy.As these studies were limited to established cell lines, we addressed this issue using a genetically defined mouse retroviral transduction/bone marrow transplantation model and observed primary murine leukemias to remain dependent on NOTCH1 signaling despite Pten loss, with or without additional deletion of p16Ink4a/p19Arf. We also examined 13 primary human T-ALL samples obtained at diagnosis and found no correlation between PTEN status and resistance to Notch inhibition. Furthermore, we noted in the mouse model that Pten loss accelerated disease onset and produced multiclonal tumors, suggesting NOTCH1 activation and Pten loss may collaborate in leukemia induction. Thus, in contrast to previous findings with established cell lines, these results indicate PTEN loss does not relieve primary T-ALL cells of their "addiction" to Notch signaling.
AB - NOTCH1 is activated by mutation in more than 50% of human T-cell acute lymphoblastic leukemias (T-ALLs) and inhibition of Notch signaling causes cell-cycle/growth arrest, providing rationale for NOTCH1 as a therapeutic target. The tumor suppressor phosphatase and tensin homolog (PTEN) is also mutated or lost in up to 20% of cases. It was recently observed among human T-ALL cell lines that PTEN loss correlated with resistance to Notch inhibition, raising concern that patients with PTEN-negative disease may fail Notch inhibitor therapy.As these studies were limited to established cell lines, we addressed this issue using a genetically defined mouse retroviral transduction/bone marrow transplantation model and observed primary murine leukemias to remain dependent on NOTCH1 signaling despite Pten loss, with or without additional deletion of p16Ink4a/p19Arf. We also examined 13 primary human T-ALL samples obtained at diagnosis and found no correlation between PTEN status and resistance to Notch inhibition. Furthermore, we noted in the mouse model that Pten loss accelerated disease onset and produced multiclonal tumors, suggesting NOTCH1 activation and Pten loss may collaborate in leukemia induction. Thus, in contrast to previous findings with established cell lines, these results indicate PTEN loss does not relieve primary T-ALL cells of their "addiction" to Notch signaling.
UR - http://www.scopus.com/inward/record.url?scp=77949527142&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77949527142&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-04-214718
DO - 10.1182/blood-2009-04-214718
M3 - Article
C2 - 20008304
AN - SCOPUS:77949527142
SN - 0006-4971
VL - 115
SP - 1175
EP - 1184
JO - Blood
JF - Blood
IS - 6
ER -