Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell leukemia

<div>Abstract<p>Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell acute lymphoblastic leukemia (T-ALL). Here, we identify a highly conserved distal enhancer (PE) that interacts with the <i>PTEN</i> promoter in multiple hematopoietic populations, including T cells, and acts as a hub of relevant transcription factors in T-ALL. Consistently, loss of PE leads to reduced <i>PTEN</i> levels in T-ALL cells. Moreover, PE-null mice show reduced <i>Pten</i> levels in thymocytes and accelerated development of NOTCH1-induced T-ALL. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by <i>Pten</i> loss. Finally, we uncovered recurrent deletions encompassing PE in T-ALL, which are associated with decreased <i>PTEN</i> levels. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.</p>Significance:<p>Here, we identify a <i>PTEN</i> enhancer that is recurrently deleted in patients with T-ALL. Loss of this enhancer leads to reduced PTEN levels in T cells together with accelerated generation and progression of NOTCH1-induced leukemia <i>in vivo</i>. These results uncover long-range regulation of tumor suppressor genes as a relevant mechanism in cancer.</p><p><i>This article is highlighted in the In This Issue feature, p. 1</i></p></div>

<p>Supplementary Figures and Tables combined</p>

<p>Supplementary Figures and Tables combined</p>

<div>Abstract<p>Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell acute lymphoblastic leukemia (T-ALL). Here, we identify a highly conserved distal enhancer (PE) that interacts with the <i>PTEN</i> promoter in multiple hematopoietic populations, including T cells, and acts as a hub of relevant transcription factors in T-ALL. Consistently, loss of PE leads to reduced <i>PTEN</i> levels in T-ALL cells. Moreover, PE-null mice show reduced <i>Pten</i> levels in thymocytes and accelerated development of NOTCH1-induced T-ALL. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by <i>Pten</i> loss. Finally, we uncovered recurrent deletions encompassing PE in T-ALL, which are associated with decreased <i>PTEN</i> levels. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.</p>Significance:<p>Here, we identify a <i>PTEN</i> enhancer that is recurrently deleted in patients with T-ALL. Loss of this enhancer leads to reduced PTEN levels in T cells together with accelerated generation and progression of NOTCH1-induced leukemia <i>in vivo</i>. These results uncover long-range regulation of tumor suppressor genes as a relevant mechanism in cancer.</p><p><i>This article is highlighted in the In This Issue feature, p. 1</i></p></div>