Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation

Abstract

A new leukaemia model has been established in mice by deleting the Pten tumour suppressor gene in fetal liver haematopoietic stem cells. The mice develop a myeloproliferative disorder that can lead to acute T lymphoblastic leukaemia. Progression of the condition is driven by leukaemia stem cells that require beta-catenin and incorporate a translocation that leads to overexpression of the c-myc oncogene, similar to findings in human acute T lymphoblastic leukaemia. The study illustrates how multiple genetic alterations can dictate hyperproliferative disorders and the progression to cancer. The loss of the Pten tumour suppressor in haematopoietic stem cells can lead to acute T lymphoblastic leukemia. This study illustrates how multi-genetic alterations can dictate hyperproliferative disorders and the progression to cancer. Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance1. The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-KitmidCD3+Lin- compartment, where unphosphorylated β-catenin is significantly increased. Conditional ablation of one allele of the β-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the β-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-KitmidCD3+Lin- LSCs and CD3+ leukaemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signalling are detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities2,3, leading to T-ALL development. Our study indicates that multiple genetic or molecular alterations contribute cooperatively to LSC transformation.