IKAROS, encoded by IKZF1, is a zinc finger transcription factor and a critical regulator of hematopoiesis. Mutations in IKZF1 have been implicated in immune deficiency, autoimmunity, and malignancy in humans. Somatic IKZF1 loss-of-function mutations and deletions have been shown to increase predisposition to the development of B cell acute lymphoblastic leukemia (B-ALL) and associated with poor prognosis. In the last 4 years, germline heterozygous IKZF1 mutations have been reported in primary immune deficiency/inborn errors of immunity. These allelic variants, acting by either haploinsufficiency or dominant negative mechanisms affecting particular functions of IKAROS, are associated with common variable immunodeficiency, combined immunodeficiency, or primarily hematologic phenotypes in affected patients. In this review, we provide an overview of genetic, clinical, and immunological manifestations in patients with IKZF1 mutations, and the molecular and cellular mechanisms that contribute to their disease as a consequence of IKAROS dysfunction.

由IKZF1编码的 IKAROS是一种锌指转录因子，是造血的关键调节因子。IKZF1的突变与人类的免疫缺陷、自身免疫和恶性肿瘤有关。体细胞IKZF1功能丧失突变和缺失已被证明会增加 B 细胞急性淋巴细胞白血病 (B-ALL) 发展的易感性，并与预后不良有关。在过去的 4 年中，种系杂合子IKZF1据报道，原发性免疫缺陷/先天性免疫缺陷有突变。这些等位基因变异，通过影响 IKAROS 特定功能的单倍体不足或显性负性机制起作用，与受影响患者的常见可变免疫缺陷、联合免疫缺陷或主要血液学表型相关。在这篇综述中，我们概述了IKZF1突变患者的遗传、临床和免疫学表现，以及 IKAROS 功能障碍导致其疾病的分子和细胞机制。