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| Blood. 2020 Aug 26. pii: 463485. doi: 10.1182/blood.2020007292 |
| Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies. |
| Kuehn HS1, Niemela JE2, Stoddard J3, Ciullini Mannurita S4, Shahin T5, Goel S6, Hintermeyer M7, Jimenez Heredi R8, Garofalo M9, Lucas L10, Singh S11, Tondo A12, Jacobs ZD13, Gahl W14, Latour S15, Verbsky J16, Routes J17, Cunningham-Rundles C18, Boztug K19, Gambineri E20, Fleisher TA21, Chandrakasan S22, Rosenzweig S23 |
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Abstract IKAROS is a transcription factor forming homo/hetero-dimers and regulating lymphocyte development and function. Germline mutations affecting IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant negative manner, cause immunodeficiency. Herein we describe four germline heterozygous IKAROS variants affecting its C-terminal dimerization domain by haploinsufficiency, in four unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome, and malignancies (T-ALL, Burkitt lymphoma). These mutations are partially or completely deficient to form homo- and hetero-dimers, but 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 of them affected the N-terminal DNA binding. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficency, 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. |
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Copyright © 2020 American Society of Hematology. |
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Publikations ID: 32845957 Quelle: öffnen |
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