Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies
Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies
复制标题
DOI：
10.1182/blood.2020007292
复制
发表时间：
2021-01-21
期刊：
影响因子：
20.3
通讯作者：
Rosenzweig, Sergio D.
中科院分区：
文献类型：
--
作者：
Kuehn, Hye Sun;Niemela, Julie E.;Rosenzweig, Sergio D.
IKAROS是一种形成同源和异源二聚体并调节淋巴细胞发育和功能的转录因子。影响IKAROS N-末端DNA结合结构域的种系突变，以单倍不足或显性阴性方式起作用，导致免疫缺陷。在此，我们描述了4个种系杂合IKAROS变异影响其C-末端二聚化结构域，通过单倍不足，在4个无关的家庭。索引患者出现血液学疾病，包括血细胞减少症（血小板减少症、贫血、中性粒细胞减少症）/Evans综合征和恶性肿瘤（T细胞急性淋巴细胞白血病、伯基特淋巴瘤）。这些二聚化缺陷突变体以完全或部分方式破坏同源和异源二聚化，但它们不影响野生型等位基因功能。此外，它们改变IKAROS基因调控的关键机制，包括SUMO化，蛋白质稳定性，以及核小体重塑和脱乙酰酶复合物的募集;不影响N-末端DNA结合缺陷。这些C-末端二聚化突变在很大程度上与血液系统疾病相关，显示二聚化单倍不足和不完全临床突变，并且在其作用机制上不同于先前报道的等位基因变体。二聚化突变体有助于IKAROS相关疾病的增长，显示基因型-表型相关性。
IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation.