Lamin B1 deletion in myeloid neoplasms causes nuclear anomaly and altered hematopoietic stem cell function.
Lamin B1 deletion in myeloid neoplasms causes nuclear anomaly and altered hematopoietic stem cell function.
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DOI：
10.1016/j.stem.2022.02.010
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发表时间：
2022-04-07
期刊：
影响因子：
23.9
通讯作者：
Doulatov, Sergei
中科院分区：
文献类型：
--
作者：
Reilly, Andreea;Creamer, J. Philip;Stewart, Sintra;Stolla, Massiel C.;Wang, Yuchuan;Du, Jing;Wellington, Rachel;Busch, Stephanie;Estey, Elihu H.;Becker, Pamela S.;Fang, Min;Keel, Sioban B.;Abkowitz, Janis L.;Soma, Lorinda A.;Ma, Jian;Duan, Zhijun;Doulatov, Sergei
异常核形态是恶性细胞的标志，广泛用于癌症诊断。Pelger-Huët异常（PHA）是髓系肿瘤（MN）中常见的中性粒细胞核形态异常，分子病因不明。我们发现，核纤层蛋白B1（LMNB 1）编码的染色体5 q上的损失，经常在MN中删除，诱导核形态和人类造血干细胞（HSC）功能与恶性肿瘤相关的缺陷。LMNB 1缺陷改变基因组组织，诱导HSC的体外和体内扩增，髓样偏向分化伴淋巴定型受损，以及由于DNA损伤修复缺陷导致的基因组不稳定性。MN患者中性粒细胞的核畸形与LMNB 1位点的5 q缺失相关，核纤层蛋白B1缺失是正常和5 q缺失中性粒细胞中引起PHA的必要和充分条件。因此，LMNB 1缺失导致获得性PHA，并通过基因组组织将异常核形态与HSC和祖细胞命运决定联系起来。异常核形态是癌细胞的标志。在这里，Reilly等人证明了在骨髓恶性肿瘤中常见的核纤层蛋白B1的缺失导致获得性Pelger-Huet核异常，并通过3D基因组组织将异常的核形态与HSC命运决定联系起来。
Abnormal nuclear morphology is a hallmark of malignant cells widely used in cancer diagnosis. Pelger-Huët anomaly (PHA) is a common abnormality of neutrophil nuclear morphology of unknown molecular etiology in myeloid neoplasms (MN). We show that loss of nuclear lamin B1 (LMNB1) encoded on chromosome 5q, frequently deleted in MN, induces defects in nuclear morphology and human hematopoietic stem cell (HSC) function associated with malignancy. LMNB1 deficiency alters genome organization inducing in vitro and in vivo expansion of HSCs, myeloid-biased differentiation with impaired lymphoid commitment, and genome instability due to defective DNA damage repair. Nuclear dysmorphology of neutrophils in MN patients is associated with 5q deletions spanning the LMNB1 locus, and lamin B1 loss is both necessary and sufficient to cause PHA in normal and 5q deleted neutrophils. LMNB1 loss thus causes acquired PHA and links abnormal nuclear morphology with HSC and progenitor cell fate determination via genome organization. Abnormal nuclear morphology is a hallmark of cancerous cells. Here, Reilly et al. demonstrate that deletion of lamin B1, common in myeloid malignancies, causes acquired Pelger-Huet nuclear anomaly and links aberrant nuclear morphology with HSC fate determination via 3D genome organization.
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