小柯机器人

美国华盛顿大学Sergei Doulatov团队发现，骨髓肿瘤中的核纤层蛋白B1缺失导致核异常和造血干细胞功能改变。这一研究成果于2022年3月11日在线发表在国际学术期刊《细胞—干细胞》上。

研究人员表示，核形态异常是广泛用于癌症诊断恶性细胞的一个标志。Pelger-Huët异常（PHA）是骨髓类肿瘤（MN）中一种常见的中性粒细胞核形态异常，其分子病因不明。

研究人员发现，在MN中经常被删除的5q染色体上编码的核纤层蛋白B1（LMNB1）会丢失，从而诱发与恶性肿瘤相关的核形态和人类造血干细胞（HSC）功能的缺陷。LMNB1的缺失改变了基因组组织，诱发了造血干细胞的体外和体内扩增，骨髓偏向性分化与淋巴谱系受损，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横跨LMNB1基因座的5q缺失有关，而核纤层蛋白B1的缺失对引起正常和5q缺失的中性粒细胞的PHA来说既是必要的也是充分的。因此，LMNB1缺失导致获得性PHA，并通过基因组组织将异常的核形态与造血干细胞和祖细胞命运决定联系起来。

附：英文原文

Title: Lamin B1 deletion in myeloid neoplasms causes nuclear anomaly and altered hematopoietic stem cell function

Author: Andreea Reilly, J. Philip Creamer, Sintra Stewart, Massiel C. Stolla, Yuchuan Wang, Jing Du, Rachel Wellington, Stephanie Busch, Elihu H. Estey, Pamela S. Becker, Min Fang, Siobán B. Keel, Janis L. Abkowitz, Lorinda A. Soma, Jian Ma, Zhijun Duan, Sergei Doulatov

Issue&Volume: 2022-03-11

Abstract: Abnormal nuclear morphology is a hallmark of malignant cells widely used in cancerdiagnosis. Pelger-Hut anomaly (PHA) is a common abnormality of neutrophil nuclearmorphology of unknown molecular etiology in myeloid neoplasms (MNs). We show thatloss of nuclear lamin B1 (LMNB1) encoded on chromosome 5q, which is frequently deletedin MNs, induces defects in nuclear morphology and human hematopoietic stem cell (HSC)function associated with malignancy. LMNB1 deficiency alters genome organization inducingin 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 ofneutrophils in patients with MNs is associated with 5q deletions spanning the LMNB1locus, and lamin B1 loss is both necessary and sufficient to cause PHA in normal and5q-deleted neutrophils. LMNB1 loss thus causes acquired PHA and links abnormal nuclearmorphology with HSCs and progenitor cell fate determination via genome organization.

DOI: 10.1016/j.stem.2022.02.010

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00061-3

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