Ikzf3

In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2 H ,4 H )-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC50 =2.25 µM) and U239 (IC50 =5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC50 =0.76 µM) in LPS stimulated PMBC and showed nearly no toxicity to this normal human cell line. The TR-FRET assay showed compound 10a having potent inhibitory activity against CRBN (IC50 =4...

Great progress has been made in improving survival in multiple myeloma (MM) patients over the last 30 years. New drugs have been introduced and complete responses are frequently seen. However, the majority of MM patients do experience a relapse at a variable time after treatment, and ultimately the disease becomes drug-resistant following therapies. Recently, minimal residual disease (MRD) detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response. MRD can be considered as a surrogate for both progression-free and overall survival...

Emerging evidence indicates that hypoxia and immunity play important roles in tumorigenesis and development. However, the hypoxia-immune-related prognostic risk model has not been established in cervical cancer (CC). We aimed to construct a hypoxia-immune-related prognostic risk model, which has potential application in predicting the prognosis of CC patients and the response to targeted therapy. The RNA-seq data and corresponding clinical information were retrieved from The Cancer Genome Atlas (TCGA) database...

WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A lysine methyltransferase complex, is critically involved in oncogenesis and represents an attractive onco-target. Inhibitors targeting protein-protein interactions (PPIs) between WDR5 and its binding partners, however, do not inhibit all of WDR5-mediated oncogenic functions and exert rather limited antitumor effects. Here, we report a cereblon (CRBN)-recruiting proteolysis targeting chimera (PROTAC) of WDR5, MS40, which selectively degrades WDR5 and the well-established neo-substrates of immunomodulatory drugs (IMiDs):CRBN, the Ikaros zinc finger (IKZF) transcription factors IKZF1 and IKZF3...

Background: Graves' disease (GD) is one of the most common autoimmune diseases worldwide and develops in 20 to 50 cases per 100,000 persons annually. Long noncoding RNAs (lncRNAs) are widely expressed in multiple human diseases and have pivotal functions in gene regulation. This study is aimed at determining the lncRNA profile in peripheral blood mononuclear cells (PBMCs) from GD patients and investigating the role of ENST00000604491 in GD. Methods: A total of 31 GD patients and 32 normal controls were enrolled in the study...

OBJECTIVES: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros ( IKZF1 ) and Aiolos ( IKZF3 ). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). METHODS: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81)...

AIOLOS is encoded by IKZF3 and is a member of the IKAROS zinc finger transcription factor family. Heterozygous missense variants in the second zinc finger of AIOLOS have recently been reported to be found in the families of patients with inborn errors of immunity. The AIOLOSG159R variant was identified in patients with B-lymphopenia and familial Epstein-Barr virus-associated lymphoma. Early B-cell progenitors were significantly reduced in the bone marrow of patients with AIOLOSG159R . Another variant, AIOLOSN160S was identified in the patients presented with hypogammaglobulinemia, susceptibility to Pneumocystis jirovecii pneumonia, and chronic lymphocytic leukemia...

The development of therapies to eliminate the latent HIV-1 reservoir is hampered by our incomplete understanding of the biomolecular mechanism governing HIV-1 latency. To further complicate matters, recent single cell RNA-seq studies reported extensive heterogeneity between latently HIV-1-infected primary T cells, implying that latent HIV-1 infection can persist in greatly differing host cell environments. We here show that transcriptomic heterogeneity is also found between latently infected T cell lines, which allowed us to study the underlying mechanisms of intercell heterogeneity at high signal resolution...

Pulmonary arterial hypertension (PAH) is a rare disorder associated with high morbidity and mortality despite currently available treatments. We compared the phosphoproteome of lung tissue from subjects with idiopathic PAH (iPAH) obtained at the time of lung transplant with control lung tissue. The mass spectrometry-based analysis found 60,428 phosphopeptide features from which 6622 proteins were identified. Within the subset of identified proteins there were 1234 phosphopeptides with q  < 0.05, many of which are involved in immune regulation, angiogenesis, and cell proliferation...

Immunomodulatory drugs are a class of drugs approved for the treatment of multiple myeloma. These compounds exert their clinical effects by inducing interactions between the CRL4CRBN E3 ubiquitin ligase and a C2H2 zinc finger degron motif, resulting in degradation of degron-containing targets. However, although many cellular proteins feature the degron motif, only a subset of those are degradable via this strategy. Here, we demonstrated that FPFT-2216, a previously reported "molecular glue" compound, degrades PDE6D, in addition to IKZF1, IKZF3, and CK1α...

Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p...

BACKGROUND: Childhood wheeze represents a first symptom of asthma. Early identification of children at risk for wheeze related to 17q12-21 variants and their underlying immunological mechanisms remain unknown. We aimed to assess the influence of 17q12-21 variants and mRNA-expression at birth on development of wheeze. METHODS: Children were classified as multitrigger-/viral-/no-wheeze until six years of age. The PAULINA/PAULCHEN birth cohorts were genotyped (n=216; GSA-chip)...

Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of 'neosubstrates', Ikaros (IKZF1) and Aiolos (IKZF3), conveying concurrent antimyeloma activity and T-cell costimulation. There is now a greater understanding of physiological CRBN functions, including endogenous substrates and chaperone activity...

AIOLOS/IKZF3 is a member of the IKAROS family of transcription factors. IKAROS/IKZF1 mutations have been previously associated with different forms of primary immunodeficiency. Here we describe a novel combined immunodeficiency due to an IKZF3 mutation in a family presenting with T and B cell involvement, Pneumocystis jirovecii pneumonia, and/or chronic lymphocytic leukemia. Patients carrying the AIOLOS p.N160S heterozygous variant displayed impaired humoral responses, abnormal B cell development (high percentage of CD21low B cells and negative CD23 expression), and abrogated CD40 responses...

Chimeric antigen receptor (CAR) T cell therapy has been successful in treating hematological malignancy, but solid tumors remain refractory. Here, we demonstrated that knocking out transcription factor IKZF3 in HER2-specific CAR T cells targeting breast cancer cells did not affect CAR expression or CAR T cell differentiation, but markedly enhanced killing of the cancer cells in vitro and in a xenograft model, which was associated with increased T cell activation and proliferation. Furthermore, IKZF3 KO had similar effects on the CD133-specific CAR T cells targeting glioblastoma cells...

Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase DNMT3A is a key regulator of DNA methylation. Although DNMT3A somatic mutations in CLL are rare, we found that low DNMT3A expression is associated with more aggressive disease. A conditional knockout mouse model showed that homozygous depletion of Dnmt3a from B cells results in the development of CLL with 100% penetrance at a median age of onset of 5...

Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy...

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma (NHL) with a dismal prognosis. The pathogenesis of MCL is complex and involves molecular alterations in various genes and pathways including the regulatory elements of the cell cycle machinery and senescence, DNA damage response pathways, and cell survival signals. Currently, Mantle Cell Lymphoma International Prognostic Index (MIPI) score and proliferative gene markers. TP53 and CDKN2A alterations are being used for the prognosis of MCL patients...

Proteasome inhibitors and immunomodulatory drugs (IMiDs) are two major types of drugs for treatment of multiple myeloma. Although different combination therapies for myeloma have been developed and achieved high responsive rate, these strategies frequently result in drug resistance. Therefore, it is necessary to explore new molecular mechanisms and therapeutic approaches to fulfill this unmet medical need. Here, we find that proteasome inhibitor bortezomib (Btz) causes cereblon (CRBN) cleavage and caspase-8 (CASP-8) is responsible for this cleavage...

Targeted protein degradation by the ubiquitin-proteasome system represents a new strategy to destroy pathogenic proteins in human diseases, including cancer and neurodegenerative diseases. The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide have revolutionized the treatment of patients with multiple myeloma (MM) and other hematologic malignancies, but almost all patients eventually develop resistance to IMiDs. CRBN, a substrate receptor of CUL4-RBX1-DDB1-CRBN (CRL4CRBN ) E3 ubiquitin ligase, is a direct target for thalidomide teratogenicity and antitumor activity of IMiDs (now known as Cereblon E3 ligase modulators: CELMoDs)...