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

Abstract

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 resistance 1 . 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-Kit mid CD3 + 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-Kit mid CD3 + Lin − LSCs and CD3 + leukaemic blasts,

It's T-ALL about Notch

“…Of the cancers that developed in PTEN þ /À mice, 88% were classified as T-ALL (Suzuki et al, 1998). Furthermore, mice reconstituted with PTEN À/À hematopoietic stem cells (HSCs) developed T-ALL that harbored translocations resulting in aberrant expression of c-myc (Guo et al, 2008). Interestingly, no activating Notch mutations were found in these tumors, however, the phenotype was the same as those tumors induced by N ICD (CD4 þ CD8 þ ), suggesting that PTEN inactivation can compensate for some Notch-mediated processes in T-ALL, namely, suppression of p53-mediated apoptosis (Figure 4).…”

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

“…12,13 There is a strong rationale for targeting PI3K/Akt/mTOR signals in T-ALL, as in mice hematopoietic stem cells, PTEN deletion (which results in PI3K/Akt/mTOR hyperactivation) led to a T-ALL. 14,15 Moreover, recent findings in a zebrafish model, have highlighted that the transition from T-lymphoblastic lymphoma to T-ALL was characterized by increased phosphorylation levels of Akt. 16 The allosteric inhibition of mTORC1 by rapamycin has only modest effects on T-ALL cells.…”

Suppression of leukemia development caused by PTEN loss

“…To investigate the molecular and cellular mechanisms associated with PTEN-controlled T-ALL pathogenesis and therapeutic resistance, we have recently developed a Pten loxP/loxP ;VE-CadherinCre + ;Rosa26 loxP-stop-loxP -LacZ + (Pten null) T-ALL mouse model by conditional deletion of Pten in a subset of fetal liver hematopoietic stem cells (8). The resulting animals develop a transient myeloproliferative disorder followed by T-ALL with 100% penetrance.…”

“…The resulting animals develop a transient myeloproliferative disorder followed by T-ALL with 100% penetrance. Besides Pten deletion, at least two subsequent spontaneous alterations, namely β-catenin activation and a Tcrα/δ-c-myc translocation, have been identified, which lead to the transformation of T-progenitor cells to self-renewable leukemia stem cells (LSCs) enriched in the c-Kit mid CD3 + Lin − subpopulation (8). Our previous work showed that this LSC subpopulation is responsible for initiating T-ALL and repopulating and maintaining leukemia development in SCID recipients on serial transplantation (8).…”