Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss.
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 p16(Ink4a)/p19(Arf). 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.
Medyouf
Hind
H
Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC.
Gao
Xiuhua
X
Armstrong
Florence
F
Gusscott
Samuel
S
Liu
Qing
Q
Gedman
Amanda Larson
AL
Matherly
Larry H
LH
Schultz
Kirk R
KR
Pflumio
Francoise
F
You
Mingjian James
MJ
Weng
Andrew P
AP
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D016026:Bone Marrow Transplantation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014161:Transduction, Genetic
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D012333:RNA, Messenger; D051881:Receptor, Notch1; D051059:PTEN Phosphohydrolase; D053829:Amyloid Precursor Protein Secretases