PTEN在胎儿肝造血干细胞（HSCs）中的丧失导致了髓系、T细胞系和B细胞系潜力的改变以及T细胞系急性淋巴细胞白血病（T-ALL）的发展。为了探索PTEN调控造血系谱选择的机制，我们使用转座酶可接近染色质测序（ATAC-seq）、单细胞RNA测序和体外培养分析在体内分离的小鼠潜在白血病HSCs和前体细胞上进行了整合的实验。我们发现PTEN丧失改变了前B前体阶段关键系谱转录因子（TF）结合位点的染色质可接触性，对应于增加的髓系和T细胞系潜力以及降低的B细胞系潜力。重要的是，我们发现PU.1是PTEN下游的一个关键转录因子，改变PU.1水平可以重编程Ptennull前B前体细胞的染色质可接触性和髓系、T细胞系和B细胞系潜力。我们的研究发现前B前体是PTEN调控的造血系谱选择的关键发育阶段，同时暗示了PU.1在调节前B前体祖细胞的表观遗传状态和系谱可塑性方面起到了重要作用。版权所有©2023 The Author(s)。由Elsevier Inc.出版。保留所有权利。

PTEN loss in fetal liver hematopoietic stem cells (HSCs) leads to alterations in myeloid, T-, and B-lineage potentials and T-lineage acute lymphoblastic leukemia (T-ALL) development. To explore the mechanism underlying PTEN-regulated hematopoietic lineage choices, we carry out integrated assay for transposase-accessible chromatin using sequencing (ATAC-seq), single-cell RNA-seq, and in vitro culture analyses using in vivo-isolated mouse pre-leukemic HSCs and progenitors. We find that PTEN loss alters chromatin accessibility of key lineage transcription factor (TF) binding sites at the prepro-B stage, corresponding to increased myeloid and T-lineage potentials and reduced B-lineage potential. Importantly, we find that PU.1 is an essential TF downstream of PTEN and that altering PU.1 levels can reprogram the chromatin accessibility landscape and myeloid, T-, and B-lineage potentials in Ptennull prepro-B cells. Our study discovers prepro-B as the key developmental stage underlying PTEN-regulated hematopoietic lineage choices and suggests a critical role of PU.1 in modulating the epigenetic state and lineage plasticity of prepro-B progenitors.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.