Familial Immune Thrombocytopenia Associated With a Novel Variant in IKZF1

Sriaroon, Panida; Chang, Yi‐Lu; Ujházi, Boglárka; Csomós, Krisztián; Joshi, Hemant R.; Zhou, Qin; Close, Devin; Walter, Jolán E.; Kumánovics, Attila

doi:10.3389/fped.2019.00139

Cited by 19 publications

(9 citation statements)

References 17 publications

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“…The disorder of its expression has the directive relationship with the hematological malignancies and primary immunodeficiency. Lack of Ikaros family may lead to a variety of immune related diseases, including immune thrombocytopenia ( Sriaroon et al, 2019 ), systemic lupus erythematosus ( Chen et al, 2020 ), rheumatoid arthritis ( Yang et al, 2019 ). For example, mutations of IKZF1–3 in leukemias are associated with poor prognosis, mainly caused by the disruption of lymphocyte fates ( Rebollo and Schmitt, 2003 ; Payne and Dovat, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Novel IKZF3 transcriptomic signature correlates with positive outcomes of skin cutaneous melanoma: A pan-cancer analysis

Yang

Lin²,

Li³

et al. 2022

Front. Genet.

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To investigate the potential relationship between Ikaros family genes and skin cutaneous melanoma (SKCM), we undertook a pan-cancer analysis of the transcriptional signature and clinical data of melanoma through multiple databases. First, 10,327 transcriptomic samples from different cancers were included to determine the overall characteristics and clinical prognoses associated with Ikaros gene expression across cancer types. Second, differentially expressed genes analysis, prognostic evaluation, and gene set enrichment analysis were employed to investigate the role of Ikaros (IKZF) genes in SKCM. Third, we evaluated the relationship between Ikaros family genes and SKCM immune infiltrates and verified the findings using the GEO single-cell sequencing dataset. The results show that Ikaros genes were widely expressed among different cancer types with independently similar patterns as follows: 1. IKZF1 and IKZF3, and 2. IKZF2 and IKZF4–5. IKZF2 and IKZF5 were downregulated in the primary tumor, and IKZF1–3 expression decreased significantly as the T-stage or metastasis increased in SKCM. Moreover, high IKZF1–3 expression was associated with better overall survival, disease-specific survival, and progression-free interval. IKZF3 is an independent prognostic factor of SKCM. Among Ikaros genes, the expression of IKZF1 and IKZF3 positively correlated with the infiltration level of CD4+ T cells and CD8+ T cells, B cells, and Tregs in SKCM and negatively correlated with the infiltration level of M0 and M1 macrophages. Moreover, single-cell sequencing data analysis revealed that IKZF1 and IKZF3 were mainly expressed by immune cells. Correlation analysis shows the immune factors and drug responses associated with IKZF3 expression. In conclusion, the present study is the first, to our knowledge, to identify a pan-cancer genomic signature of the Ikaros gene family among different cancers. Expression of these family members, particularly high levels of IKZF3, indicate positive immunological status and beneficial clinical outcomes of SKCM. IKZF3 may therefore serve as potential targets for immunotherapy of melanoma.

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Section: Discussionmentioning

confidence: 99%

Novel IKZF3 transcriptomic signature correlates with positive outcomes of skin cutaneous melanoma: A pan-cancer analysis

Yang

Lin²,

Li³

et al. 2022

Front. Genet.

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“…Most IKAROS mutations result in a greatly increased susceptibility to infectious diseases, whether or not in combination with autoimmune diseases. Sometimes autoimmune diseases, such as ITP, SLE, and IBD are in the foreground ( 7 , 20 – 22 ), while in others, these germline mutations can give rise to B- or T-cell leukemia ( 7 , 17 , 18 , 23 ), in which an absolute predictive parameter or genotype–phenotype relationship is still elusive.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Highly Variable Clinical and Immunological Presentation of IKAROS Deficiency in a Single Family

et al. 2022

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Here we describe a novel mutation in the IKZF gene encoding IKAROS, as the cause of common variable immunodeficiency (CVID). The identification of the same defect in the IKZF gene with manifestations of asymptomatic selective IgA deficiency and chronic ITP in the father and her younger brother, respectively, demonstrates the large variability of this genetic defect in one single family, while living in the same environment with a relatively similar genetic background. As discussed, clinical penetrance of the molecular defects identified by mutations in IKZF and other common gene defects in CVID in familial immune-related abnormalities makes genetic testing a necessary step for diagnosis, management, and counseling, as part of the routine immunological workup.

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“…All germline heterozygous IKZF1 allelic variants reported so far (i.e., HI, DN) and herein (i.e., DD), are associated with certain clinical phenotypes. While patients with DN mutations present with a T-and B-cell CID phenotype mainly characterized by opportunistic infections (7/7) 23 , patients carrying HI mutations present primarily with a CVID picture of increased susceptibility to B-cell immunity-controlled infections (~60%) [16][17][18][19][20][21][22]40 ; patients with DD mutations, most typically present with hematologic dyscracias (38%, 5/13; cytopenias in 4, malignancies in 2).…”

Section: Ipa Pathway Analysis Revealed That While Functions Associated With Malignant Tumormentioning

confidence: 99%

“…Recently, we and others reported germline heterozygous IKZF1 allelic variants associated with specific immunological phenotypes. The phenotypes consisted of a common variable immunodeficiency (CVID)-like presentation with progressive B-cell loss, hypogammaglobulinemia and antibody dysfunction, along with recurrent and severe bacterial infections; B-ALL susceptibility and autoimmune manifestations were also observed 12, [16][17][18][19][20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies

Kuehn

Niemela

Stoddard

et al. 2021

Blood

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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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Familial Immune Thrombocytopenia Associated With a Novel Variant in IKZF1

Cited by 19 publications

References 17 publications

Novel IKZF3 transcriptomic signature correlates with positive outcomes of skin cutaneous melanoma: A pan-cancer analysis

Novel IKZF3 transcriptomic signature correlates with positive outcomes of skin cutaneous melanoma: A pan-cancer analysis

Case Report: A Highly Variable Clinical and Immunological Presentation of IKAROS Deficiency in a Single Family

Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies

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