Ikzf1

BACKGROUND: To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved. METHODS: Based on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes...

BACKGROUND: Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections. METHODS: We studied seven relatives with autoimmune/inflammatory diseases and lymphoproliferative diseases. We analysed biopsy results and performed whole-exome sequencing and immunological studies...

B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common childhood cancers worldwide. Although most cases are sporadic, some familial forms, inherited as autosomal dominant traits with incomplete penetrance, have been described over the last few years. Germline pathogenic variants in transcription factors such as PAX5, IKZF1 , and ETV6 have been identified as causal in familial forms. The proband was a 7-year-old Mexican girl diagnosed with high-risk B-ALL at five years and 11 months of age. Family history showed that the proband's mother had high-risk B-ALL at 16 months of age...

Comprehending the mechanism behind human diseases with an established heritable component represents the forefront of personalized medicine. Nevertheless, numerous medically important genes are inaccurately represented in short-read sequencing data analysis due to their complexity and repetitiveness or the so-called "dark regions" of the human genome. The advent of PacBio as a long-read platform has provided new insights, yet HiFi whole-genome sequencing (WGS) cost remains frequently prohibitive. We introduce a targeted sequencing and analysis framework, Twist Alliance Dark Genes Panel (TADGP), designed to offer phased variants across 389 medically important yet complex autosomal genes...

UNLABELLED: Immunomodulatory imide drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein of interest that is fused to a short zinc finger (ZF) degron motif. These IMiDs, however, also induce degradation of endogenous neosubstrates, including IKZF1 and IKZF3. To improve degradation selectivity, we took a bump-and-hole approach to design and screen bumped IMiD analogs against 8380 ZF mutants. This yielded a bumped IMiD analog that induces efficient degradation of a mutant ZF degron, while not affecting other cellular proteins, including IKZF1 and IKZF3...

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is characterized by highly genetic heterogeneity, owing to recurrent fusion genes, gene mutations, intragenic deletion, and gene overexpression, which poses significant challenges in clinical detection. RNA sequencing (RNA-seq) is a powerful tool for detecting multiple genetic abnormalities, especially cryptic gene rearrangements, in a single test. METHODS: Sixty samples (B-ALL, n = 49; T-ALL, n = 9; mixed phenotype acute leukemia (MPAL), n = 2) and 20 controls were analyzed by targeted RNA-seq panel of 507 genes developed by our lab...

B cell acute lymphoblastic leukemia (ALL) is characterized by the highly heterogeneity of pathogenic genetic background, and there are still approximately 30-40% of patients without clear molecular markers. To identify the dysregulated genes in B cell ALL, we screened 30 newly diagnosed B cell ALL patients and 10 donors by gene expression profiling chip. We found that ECM1 transcription level was abnormally elevated in newly diagnosed B cell ALL and further verified in another 267 cases compared with donors (median, 124...

Mezigomide is an oral cereblon E3 ligase modulator (CELMoD) that is under clinical investigation in patients with relapsed/refractory (RR) multiple myeloma (MM). Like other CELMoD compounds, mezigdomide acts by altering the conformation of cereblon within the cullin 4A ring ligase-cereblon (CRL4CRBN) E3 ubiquitin ligase complex, thereby recruiting novel protein substrates for selective proteasomal degradation. These include two critical lymphoid transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), also known as Ikaros and Aiolos, which have important roles in the development and differentiation of hematopoietic cells, in MM pathobiology, and in suppressing the expression of interferon-stimulating genes and T-cell stimulation...

Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0...

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription...

INTRODUCTION: The genetic heterogeneity of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) mutations may affect clinical responses and outcomes to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aims to investigate the genomic factors that influence the efficacy and clinical outcomes of first-line, second-line and third-line treatments in NSCLC and explore the heterogeneity of resistance mechanisms. MATERIALS AND METHODS: This real-world study comprised 65 patients with EGFR mutant NSCLC...

The demographic factors, the socioeconomic status and the ethnicity of populations are important players that determine the incidence, the prevalence and the spectrum of systemic lupus erythematosus (SLE) clinical presentations in different populations. Therefore, the purpose of the present research was to investigate the possible association between the Ikaros family zinc finger 1 gene (IKZF1) rs4132601 and rs11978267 single nucleotide polymorphisms (SNPs) and SLE susceptibility and clinical presentations including lupus nephritis (LN) among Egyptian paediatric patients...

This study investigates the potential utility of IKZF1 deletion as an additional high-risk marker for paediatric acute lymphoblastic leukaemia (ALL). The prognostic impact of IKZF1 status, in conjunction with minimal/measurable residual disease (MRD), was evaluated within the MRD-guided TPOG-ALL-2013 protocol using 412 newly diagnosed B-ALL patients aged 1-18. IKZF1 status was determined using multiplex ligation-dependent probe amplification. IKZF1 deletions, when co-occurring with CDKN2A, CDKN2B, PAX5 or PAR1 region deletions in the absence of ERG deletions, were termed IKZF1plus ...

BACKGROUND: Immune dysregulation often presents as autoimmunity, inflammation and/or lymphoproliferation. Several germline genetic defects have been associated with immune dysregulation including heterozygous gain-of-function (GOF) mutations in IKZF1, an essential transcription factor for hematopoiesis containing zinc finger domains (ZFs). However, in a large part of patients the genetic origin of their immunedysregulation remains undetermined. OBJECTIVE: A family with two members presenting immune dysregulation signs was studied to identify the genetic cause of their disease...

BACKGROUND: Colorectal cancer (CRC) has a high rate of recurrence, in particular for advanced disease, but prognosis based on staging and pathology at surgery can have limited efficacy. The presence of circulating tumor DNA (ctDNA) at diagnosis could be used to improve the prediction for disease recurrence. OBJECTIVES: To assess the impact of detecting methylated BCAT1/IKZF1 ctDNA at diagnosis in combination with demographic, lifestyle, clinical factors and tumor pathology, to assess predictive value for recurrence...

Monogenic diseases of immune dysregulation should be considered in the evaluation of children presenting with recurrent neutrophilic dermatoses in association with systemic signs of inflammation, autoimmune disease, hematologic abnormalities, and opportunistic or recurrent infections. We report the case of a 2-year-old boy presenting with a neutrophilic dermatosis, found to have a novel likely pathogenic germline variant of the IKAROS Family Zinc Finger 1 (IKZF1) gene; the mutation likely results in a loss of function dimerization defective protein based on reports and studies of similar variants...

Acute lymphoblastic leukemia (ALL) with fusions of ABL-class tyrosine kinase genes other than BCR::ABL1 occurs in approximately 3% of children with ALL. The tyrosine kinase genes involved in this BCR::ABL1-like (Ph-like) subtype include ABL1, PDGFRB, ABL2, and CSF1R, which each have up to ten described partner genes. ABL-class ALL resembles BCR::ABL1-positive ALL by a similar gene expression profile, a poor response to chemotherapy, and sensitivity to tyrosine kinase inhibitors (TKIs). There is a lack of comprehensive data regarding TKI sensitivity for the heterogeneous group of ABL-class ALL...

Sulfonyl fluoride EM12-SF was developed previously to covalently engage a histidine residue in the sensor loop of cereblon (CRBN) in the E3 ubiquitin ligase complex CRL4CRBN . Here, we further develop the structure-activity relationships of additional sulfonyl fluoride containing ligands that possess a range of cereblon binding potencies in cells. Isoindoline EM364-SF, which lacks a key hydrogen bond acceptor present in CRBN molecular glues, was identified as a potent binder of CRBN. This led to the development of the reversible molecular glue CPD-2743, that retained cell-based binding affinity for CRBN and degraded the neosubstrate IKZF1 to the same extent as EM12, but unlike isoindolinones, lacked SALL4 degradation activity (a target linked to teratogenicity)...

A better understanding of ABL1-kinase domain mutation-independent causes of tyrosine kinase inhibitor (TKI) resistance is needed for BCR::ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). While TKIs have dramatically improved outcomes, a subset of patients still experiences relapsed or refractory disease. We aimed to identify potential biomarkers for intrinsic TKI resistance at diagnosis in 32 pediatric and 19 adult BCR::ABL1-positive BCP-ALL samples. Reduced ex vivo imatinib sensitivity was observed in cells derived from newly diagnosed patients who relapsed after combined TKI and chemotherapy treatment compared with cells derived from patients who remained in continuous complete remission...

Introduction: Acute lymphoblastic leukemia (ALL) is a prevalent childhood cancer with high cure rate, but poses a significant medical challenge in adults and relapsed patients. Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype, with approximately half of cases characterized by CRLF2 overexpression and frequent concomitant IKZF1 deletions. Methods: To address the need for efficient, rapid, and cost-effective detection of CRLF2 alterations, we developed a novel RT-qPCR technique combining SYBR Green and highresolution melting analysis on a single plate...