Data from PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i>-Deficient Hematopoiesis from Malignant Transformation

Abstract

<div>Abstract<p>Cytosine hypermethylation in and around DNA-binding sites of master transcription factors, including PU.1, occurs in aging hematopoietic stem cells following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase ten–eleven translocation-2 (TET2), albeit functional relevance has been unclear. We show that <i>Tet2</i>-deficient mouse hematopoietic stem and progenitor cells undergo malignant transformation upon compromised gene regulation through heterozygous deletion of an upstream regulatory region (URE<sup>Δ/WT</sup>) of the PU.1 gene. Although compatible with multilineage blood formation at young age, <i>Tet2</i>-deficient PU.1 URE<sup>Δ/WT</sup> mice develop highly penetrant, transplantable acute myeloid leukemia (AML) during aging. Leukemic stem and progenitor cells show hypermethylation at putative PU.1-binding sites, fail to activate myeloid enhancers, and are hallmarked by a signature of genes with impaired expression shared with human AML. Our study demonstrates that Tet2 and PU.1 jointly suppress leukemogenesis and uncovers a methylation-sensitive PU.1-dependent gene network as a unifying molecular vulnerability associated with AML.</p>Significance:<p>We identify moderately impaired PU.1 mRNA expression as a biological modality predisposing <i>Tet2</i>-deficient hematopoietic stem and progenitor cells to malignant transformation. Our study furthermore uncovers a methylation-sensitive PU.1 gene network as a common feature of myeloid leukemia potentially allowing for the identification of patients at risk for malignant transformation.</p><p><i><a href="https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-22-0100" target="_blank">See related commentary by Schleicher and Pietras, p. 378</a>.</i></p><p><i><a href="https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-3-5-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 369</a></i></p></div>