PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice.
The tumor suppressor gene phosphatase and tensin homolog (PTEN) is inactivated in many human cancers. However, it is unknown whether PTEN functions as a tumor suppressor in human Philadelphia chromosome-positive leukemia that includes chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL) and is induced by the BCR-ABL oncogene. By using our mouse model of BCR-ABL-induced leukemias, we show that Pten is down-regulated by BCR-ABL in leukemia stem cells in CML and that PTEN deletion causes acceleration of CML development. In addition, overexpression of PTEN delays the development of CML and B-ALL and prolongs survival of leukemia mice. PTEN suppresses leukemia stem cells and induces cell-cycle arrest of leukemia cells. Moreover, PTEN suppresses B-ALL development through regulating its downstream gene Akt1. These results demonstrate a critical role of PTEN in BCR-ABL-induced leukemias and suggest a potential strategy for the treatment of Philadelphia chromosome-positive leukemia.
Peng
Cong
C
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Chen
Yaoyu
Y
Yang
Zhongfa
Z
Zhang
Haojian
H
Osterby
Lori
L
Rosmarin
Alan G
AG
Li
Shaoguang
S
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D025521:Tumor Suppressor Proteins; D016044:Fusion Proteins, bcr-abl; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse