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A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia

ABSTRACT: Long-range oncogenic enhancers play an important role in cancer. Yet, it remains unclear whether similar regulation of tumor suppressor genes is relevant. In this context, loss of expression of the tumor suppressor PTEN is associated with the pathogenesis of various cancers, including T-cell acute lymphoblastic leukemia (T-ALL). Here, we demonstrate that PTEN is regulated in T-cells by a distal enhancer (PE), which is targeted by recurrent focal deletions in T-ALL. This highly conserved regulatory element interacts with and transactivates the PTEN promoter. Consistently, PE deletion in T-ALL cells leads to reduced PTEN levels and proliferative advantage. Moreover, PE-null mice show reduced PTEN levels in the thymus and develop NOTCH1-induced T-ALL with faster kinetics. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by Pten loss. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE160427 | GEO | 2020/12/17

REPOSITORIES: GEO

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Project description:Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts. Crypts contain intestinal stem cells (ISCs). Thus intestinal polyposis provides an ideal condition for studying stem cell involvement in polyp/tumor formation. Using a conditional knock-out mouse model, we found that the tumor suppressor Phosphatase of Tension homolog (PTEN) governs the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN mutants, excess ISCs initiate de-novo crypt formation and crypt fission, recapitulating crypt production in fetal/neonatal intestine. Microarray studies were used to profile the changes in gene expression that occurred when PTEN was knocked out in the intestine. Experiment Overall Design: A conditional PTEN mutant allele [Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186-2189 (2001).] was combined with in interferon inducible Mx1-Cre [Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427-1429 (1995).] to enable PTEN to be deleted from the intestine by administration of polyinosinicâ??polycytidylic acid (Poly I:C). PolyI:C was administered at weaning (every other day, five times total) to three PTEN mutant (Mx1-Cre positive:PTENfx/fx) and two control (Mx1-Cre negative:PTENfx/+) animals. Intestinal polyps (from PTEN mutants) and equivalent regions of intestine (from controls) were isolated 30 days after the final polyI:C injection. Microarray analysis compared the gene expression profiles of PTEN mutant polyps and control intestines. Genes were considered up-regulated or down-regulated if all of the following conditions were met: 1) There was at least a two-fold change in the average probe signal measured between controls and mutants; 2) There was no overlap between the range of mutant and control data; and 3) The control mean was outside the 95% confidence interval of the PTEN-mutant mean.

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A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia

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