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 (MNs). We show that loss of nuclear lamin B1 (LMNB1) encoded on chromosome 5q, which is frequently deleted in MNs, 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 patients with MNs 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 HSCs and progenitor cell fate determination via genome organization.

核形态异常是广泛用于癌症诊断的恶性细胞的标志。 Pelger-Huët 异常 (PHA) 是骨髓肿瘤 (MN) 中一种常见的中性粒细胞核形态异常，分子病因未知。我们发现，编码在 5q 染色体上的核纤层蛋白 B1 (LMNB1) 的缺失（在 MN 中经常被删除）会导致与恶性肿瘤相关的核形态和人类造血干细胞 (HSC) 功能缺陷。 LMNB1 缺陷会改变基因组组织，诱导 HSC体外和体内扩增、淋巴定向受损的骨髓偏向分化，以及 DNA 损伤修复缺陷导致的基因组不稳定。 MN 患者中性粒细胞的核形态异常与跨越 LMNB1 位点的 5q 缺失相关，核纤层蛋白 B1 缺失对于正常和 5q 缺失的中性粒细胞中引起 PHA 是必要且充分的。因此，LMNB1 缺失会导致获得性 PHA，并将异常的核形态与 HSC 以及通过基因组组织决定的祖细胞命运联系起来。