Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.

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,

No abstract

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase. PTEN inhibits the action of phosphatidylinositol-3-kinase and reduces the levels of phosphatidylinositol triphosphate, a crucial second messenger for cell proliferation and survival, as well as insulin signaling. In this study, we deleted Pten specifically in the insulin producing ␤ cells during murine pancreatic development. Pten deletion leads to increased cell proliferation and decreased cell death, without significant alteration of ␤-cell differentiation. Consequently, the mutant pancreas generates more and larger islets, with a significant increase in total ␤-cell mass. PTEN loss also protects animals from developing streptozotocin-induced diabetes. Our data demonstrate that PTEN loss in ␤ cells is not tumorigenic but beneficial. This suggests that modulating the PTEN-controlled signaling pathway is a potential approach for ␤-cell protection and regeneration therapies.␤ cells are produced through neogenesis from precursor cells and/or replication of mature and differentiated ␤ cells. During embryonic development, both neogenesis and replication contribute to the growth of the pancreas. The proliferation rate of ␤ cells in the adult pancreas, however, is relatively low. The adult pancreas undergoes slow turnover, with only approximately 0.5% mitotic activity, primarily by replication of differentiated cells (16). Nutrient and growth factors, such as high glucose concentrations, insulin-like growth factor 1 (IGF-1), and growth hormone, can induce ␤-cell replication (6, 39). Adult ␤-cell proliferation has been observed among pregnant and obese individuals for whom the demand for insulin is increased (40). During ␤-cell or pancreatic injuries, mitotic activity of ␤ cells is also increased (4,6,7,20,22,40). It has been suggested that after injury, ␤-cell regeneration may be the result of progenitor cell proliferation and differentiation (5). However, recent findings by Dor et al. suggest that in murine islets, proliferation of preexisting ␤ cells is the major mechanism for regeneration under both physiological and injury conditions (15). Together, these findings suggest that ␤ cells in pancreatic islets have a significant potential for replication. However, little is known about the factors regulating ␤-cell mass during neogenesis and adult pancreas turnover.Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is an indispensable regulator for cell growth and survival (48, 51). PTEN functions as a lipid phosphatase to dephosphorylate phosphatidylinositol triphosphate, the product of phosphatidylinositol-3-kinase (PI3K) (35, 56). By antagonizing PI3K function, PTEN inhibits the signals of insulin, IGF-1, and platelet-derived growth factor, the major mitogenic and survival factors of ␤ cells (13). As a consequence of PTEN loss, AKT serine/threonine kinase and its downstream effectors are hyperactivated (48,51). AKT is critical for ␤-cell survival both in vitro and in transplantation models (1,10,12,33,34,46,54). Re...

Background Continual expression of PD-L1 in tumor cells is critical for tumor immune escape and host T cell exhaustion, however, knowledge on its clinical benefits through inhibition is limited in breast cancer. N6-methyladenosine (m6A) plays a crucial role in multiple biological activities. Our study aimed to investigate the regulatory role of the m6A modification in PD-L1 expression and immune surveillance in breast cancer. Methods MeRIP-seq and epitranscriptomic microarray identified that PD-L1 is the downstream target of METTL3. MeRIP-qPCR, absolute quantification of m6A modification assay, and RIP-qPCR were used to examine the molecular mechanism underlying METTL3/m6A/IGF2BP3 signaling axis in PD-L1 expression. B-NDG and BALB/c mice were used to construct xenograft tumor models to verify the phenotypes upon METTL3 and IGF2BP3 silencing. In addition, breast cancer tissue microarray was used to analyze the correlation between PD-L1 and METTL3 or IGF2BP3 expression. Results We identified that PD-L1 was a downstream target of METTL3-mediated m6A modification in breast cancer cells. METTL3 knockdown significantly abolished m6A modification and reduced stabilization of PD-L1 mRNA. Additionally, METTL3-mediated PD-L1 mRNA activation was m6A-IGF2BP3-dependent. Moreover, inhibition of METTL3 or IGF2BP3 enhanced anti-tumor immunity through PD-L1-mediated T cell activation, exhaustion, and infiltration both in vitro and in vivo. PD-L1 expression was also positively correlated with METTL3 and IGF2BP3 expression in breast cancer tissues. Conclusion Our study suggested that METTL3 could post-transcriptionally upregulate PD-L1 expression in an m6A-IGF2BP3-dependent manner to further promote stabilization of PD-L1 mRNA, which may have important implications for new and efficient therapeutic strategies in the tumor immunotherapy.