Knox Ainsley V C, Cominsky Lauren Y, Sun Di, Cruz Cabrera Emylette, Nolan Brian E, Ofray Edann, Benetti Elisa, Visconti Camilla, Barzaghi Federica, Rosenzweig Sergio D, Lawrence Monica G, Sullivan Kathleen E, Yoon Samuel, Rachimi Suzanna, Padem Nurcicek, Conboy Erin, Stojanovic Maja, Petrovic Gordana, Pasic Srdjan, Church Joseph, Ferdman Ronald M, Candotti Fabio, Arlabosse Tiphaine, Theodoropoulou Katerina, Dutmer Cullen M, Maródi László, Szücs Gabriella, Broides Arnon, Nahum Amit, Levy Jacov, Kettunen Kaisa, Daddali Ravindra, Seppänen Mikko, Vänttinen Markku, Martelius Timi, Grönholm Juha, Peri Matilde, Azzari Chiara, Ricci Silvia, Ojaimi Samar, Edwards Emily S J, van Zelm Menno C, Sun Jinqiao, Abolhassani Hassan, Pan-Hammarström Qiang, Hakonarson Hakon, Mayr Daniel, Boztug Kaan, Boisson Bertrand, Casanova Jean-Laurent, Le Coz Carole, Poon Gregory M K, Romberg Neil
Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.
Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Blood. 2025 May 29;145(22):2549-2560. doi: 10.1182/blood.2024026683.
Leukopoiesis is lethally arrested in mice lacking the master transcriptional regulator PU.1. Depending on the animal model, subtotal PU.1 loss either induces acute myeloid leukemia or arrests early B-cell and dendritic-cell development. Although humans with absolute PU.1 deficiency have not been reported, a small cadre of congenital agammaglobulinemia patients with sporadic, inborn PU.1 haploinsufficiency was recently described. To better estimate the penetrance, clinical complications, immunophenotypic features, and malignancy risks of PU.1-mutated agammaglobulinemia (PU.MA), a collection of 134 novel or rare PU.1 variants from publicly available databases, institutional cohorts, previously published reports, and unsolved agammaglobulinemia cases were functionally analyzed. In total, 25 loss-of-function (LOF) variants were identified in 33 heterozygous carriers from 21 kindreds across 13 nations. Of individuals harboring LOF PU.1 variants, 22 were agammaglobulinemic, 5 displayed antibody deficiencies, and 6 were unaffected, indicating an estimated disease penetrance of 81.8% with variable expressivity. In a cluster of patients, disease onset was delayed, sometimes into adulthood. All LOF variants conveyed effects via haploinsufficiency, either by destabilizing PU.1, impeding nuclear localization, or directly interfering with transcription. PU.MA patient immunophenotypes consistently demonstrated B-cell, conventional dendritic-cell, and plasmacytoid dendritic-cell deficiencies. Associated infectious and noninfectious symptoms hewed closely to X-linked agammaglobulinemia and not monogenic dendritic-cell deficiencies. No carriers of LOF PU.1 variants experienced hematologic malignancies. Collectively, in vitro and clinical data indicate heterozygous LOF PU.1 variants undermine humoral immunity but do not convey strong leukemic risks.
在缺乏主要转录调节因子PU.1的小鼠中，白细胞生成会受到致命性阻滞。根据动物模型的不同，PU.1部分缺失要么诱发急性髓系白血病，要么阻滞早期B细胞和树突状细胞的发育。虽然尚未报道过绝对缺乏PU.1的人类病例，但最近描述了一小群患有散发性先天性PU.1单倍体不足的先天性无丙种球蛋白血症患者。为了更好地评估PU.1突变型无丙种球蛋白血症（PU.MA）的外显率、临床并发症、免疫表型特征和恶性肿瘤风险，对来自公开数据库、机构队列研究、既往发表报告以及未解决的无丙种球蛋白血症病例中的134个新的或罕见的PU.1变体进行了功能分析。总共在来自全球13个国家的21个家族的33名杂合携带者中鉴定出25个功能丧失（LOF）变体。在携带LOF PU.1变体的个体中，22人患有无丙种球蛋白血症，5人表现出抗体缺陷，6人未受影响，这表明估计疾病外显率为81.8%，且具有可变的表达性。在一组患者中，疾病发病延迟，有时会延迟到成年期。所有LOF变体都是通过单倍体不足发挥作用的，要么是通过使PU.1不稳定、阻碍核定位或者直接干扰转录来实现。PU.MA患者的免疫表型始终显示出B细胞、传统树突状细胞和浆细胞样树突状细胞缺陷。相关的感染性和非感染性症状与X连锁无丙种球蛋白血症密切相关，而与单基因树突状细胞缺陷无关。没有LOF PU.1变体的携带者发生血液系统恶性肿瘤。总体而言，体外和临床数据表明，杂合性LOF PU.1变体破坏体液免疫，但不会带来强烈的白血病风险。
