Identification of germline monoallelic mutations in <i>IKZF2</i> in patients with immune dysregulation

Shahin, Tala; Mayr, Daniel; Shoeb, Mohamed R.; Hoeger, Birgit; Giuliani, Sarah; Gawriyski, Lisa; Petronczki, Özlem Yüce; Hadjadj, Jérôme; Bal, Sevgi Köstel; Zoghi, Samaneh; Haimel, Matthias; Heredia, Raúl Jimenez; Boutboul, David; Triebwasser, Michael; Rialland-Battisti, Fanny; Costédoat-Chalumeau, Nathalie; Quartier, Pierre; Tangye, Stuart G.; Fleisher, Thomas A.; Rezaei, Nima; Romberg, Neil; Latour, Sylvain; Varjosalo, Markku; Halbritter, Florian; Rieux‐Laucat, Frédéric; Castanon, Irinka; Rosenzweig, Sergio D.; Boztuğ, Kaan

doi:10.1182/bloodadvances.2021006367

Cited by 32 publications

(30 citation statements)

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“…PAX1 [13,14], ITPKB [15]; SASH3 [16,17], MAN2B2 [18], COPG1 [19], IKZF2 [20][21][22][23], CHUK [24], IKZF3 [25,26], CRACR2A [27], CD28 [28]) (Table 1; Supplementary Table 1); • Combined immunodeficiencies with syndromic features (MCM10 [29,30], IL6ST [31][32][33], DIAPH1 [34]) (Table 2; Supplementary Table 1); • B cell deficiencies, agammaglobulinemia, or hypogammaglobulinemia (FNIP1 [35,36], SP1I [37], PIK3CG [38,39], POU2AF1 [40], CTNNBL1 [41], TNSRSF13 [42]) (Table 3; Supplementary Table 1); • Immune dysregulation (RHOG [43], SOCS1 [44][45][46],…”

Section: Novel Inborn Errors Of Immunitymentioning

confidence: 99%

“…• The IKAROS family of proteins -IKAROS, AIO-LOS, and HELIOS -interacts with one another as homodimers, heterodimers, or heterotrimers to regulate immune cell development and function [109]. While variants in IKZF1 encoding IKAROS have been previously reported [5,109], individuals have now been identified with pathogenic variants in IKZF2 (HELIOS) [20][21][22][23] and IKZF3 (AIOLOS) [25,26], as well as GOF variants in IKZF1 [52]. While these genotypes present with some distinct clinical phenotypes, there is also substantial overlap, such as B cell deficiency, hypo-or agammaglobulinemia, recurrent infections, and predisposition to B cell malignancy.…”

Section: Novel Iei Phenocopy Known Iei Confirming Critical Pathways F...mentioning

confidence: 99%

“…The discovery of novel IEI continues to demonstrate that distinct types of variants (GOF, LOF, mono-allelic, biallelic, exon splicing) in the same gene can cause disparate clinical conditions. This update includes AR and AD forms of IKZF2 (HELIOS) [20][21][22][23] and IL6ST [31][32][33] deficiency, as well as AD RIPK1 LOF [85,86], AR GOF TMEM173/ STING [70], AR LOF TBK1 [82], and mono-allelic IKZF1 GOF [52] variants which complement previous reports of AR RIPK1 deficiency, AD GOF TMEM173/STING, AD TBK1 deficiency, and mono-allelic IKZF1 inactivating variants, respectively [5]. AR GOF variants in CEBPE also represent a novel IEI [51].…”

Section: One Gene Several Phenotypesmentioning

confidence: 99%

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Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

et al. 2022

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We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

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Section: Novel Inborn Errors Of Immunitymentioning

confidence: 99%

Section: Novel Iei Phenocopy Known Iei Confirming Critical Pathways F...mentioning

confidence: 99%

Section: One Gene Several Phenotypesmentioning

confidence: 99%

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Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

et al. 2022

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“…The heterozygous and homozygous germline variants of HELIOS have been recently identified in the patients with recurrent sinopulmonary infections, chronic Candida infection, hypogammaglobulinemia, and lymphoma ( 18 , 19 ). Heterozygous HELIOS variants have also recently been reported in patients with autoimmune diseases such as systemic lupus erythematosus, and Epstein–Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis ( 20 ). In addition, heterozygous PEGASUS variants have been identified in a cohort with hereditary thrombocytopenia ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

AIOLOS Variants Causing Immunodeficiency in Human and Mice

Yamashita

Morio

2022

Front. Immunol.

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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. Patients with AIOLOSN160S had mostly normal B cell counts but showed increased levels of CD21lo B cells, decreased CD23 expression, and abrogated CD40 response. Both variants were determined to be loss-of-function. Mouse models harboring the corresponding patient’s variants recapitulated the phenotypes of the patients. AIOLOS is therefore a novel disease-causing gene in human adaptive immune deficiency.

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“…Recent evidence has further implicated IKZF2 in dysfunctional Teff cells in tumors 13,14 . Germline mutations of IKZF2 in humans have also recently been associated with chronic T cell activation and increased production of pro-in ammatory cytokines both in effector and regulatory T cells 15,16 . Taken together, these data suggest that degradation of IKZF2 in Tregs and other T cells may enhance the anti-tumor immune response, making IKZF2 an attractive target for cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Targeted degradation of IKZF2 for cancer immunotherapy

Solomon

Bonazzi

d’Hennezel

et al. 2022

Preprint

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Growing malignant tumors must evade destruction by the immune system, a hurdle some malignancies overcome by attracting immune-suppressive regulatory T-cells (Tregs)1. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Tregs, and IKZF2 deficiency enhances immune responses to tumors in mice2, suggesting IKZF2 may be an attractive target for cancer immunotherapy. Here we describe the discovery and characterization of DKY709, the first molecular glue degrader of IKZF2/4 which spares IKZF1/3. DKY709 was identified through a recruitment-guided medicinal chemistry campaign that redirected the degradation selectivity of CRBN binders towards IKZF2. The IKZF transcription factor selectivity of DKY709 was rationalized by the X-ray structure of the CRBN-DKY709-IKZF2(ZF2) ternary complex. Upon exposure to DKY709, human Tregs showed reduced suppressive activity and exhausted T-effector cells recovered IFNγ production. In vivo, oral treatment with DKY709 drove a rapid and sustained degradation of IKZF2 including in humans and led to delayed tumor growth in mice with humanized immune systems and enhanced immunization responses in monkeys. DKY709 is a first-in-class, potent and selective oral IKZF2/4 degrader currently being investigated in a phase 1 clinical trial as an immune-enhancing agent for cancer immunotherapy.

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Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation

Cited by 32 publications

References 32 publications

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

AIOLOS Variants Causing Immunodeficiency in Human and Mice

Targeted degradation of IKZF2 for cancer immunotherapy

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