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.
Chromosomal instabilities (CIN) manifesting as structural or numerical alterations in the chromosomes are common in malignancies like breast cancer. Assessment of CIN in breast cancer may help to understand its etiopathogenesis. Micronucleus (MN) scoring and aneuploidy have been used to assess the presence of CIN in lymphocytes of various malignancies in the past. In this study, spontaneously occurring MN were counted in epithelial cells on fine needle aspiration cytology (FNAC) smears from 50 patients with benign and malignant breast lesions. Further, the ploidy status and S-phase fraction (SPF) of the samples was determined by flow cytometry. All these were then correlated with grades of breast cancer at cytology. Most IDC cases showed variable number of MN (n = 16, MN mean = 9.3), in contrast to the benign lesions (n = 26) where they were consistently absent. Aneuploidy and SPF analysis also showed a significant difference between benign (n = 10, mean DNA index [DI] = 0.96 ± 0.04, mean SPF= 8.07% ± 2.93) and malignant (n = 10, mean DI = 1.5 ± 0.41, mean SPF = 25.05% ± 10.35) lesions. On statistical analysis, a positive correlation was observed between the grades of IDC and presence of aneuploidy and high SPF (P-values < 0.05); however, the difference between the MN scores of grade 2 and 3 cancers was not significant. The study suggests that MN scoring and aneuploidy may be used to assess the presence of underlying CIN in IDC on FNAC smears. Further, collectively they may be explored for their role as biomarkers for predicting the tumor behavior in the breast cancer patients.
Increased serum levels of circulating Th17 cells and related cytokines may contribute to the cutaneous pathology of psoriasis, as well as the inflammatory process that is a hallmark of psoriasis.
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