Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency
David Boutboul
(1)
,
Hye Sun Kuehn
(2)
,
Zoé van de Wyngaert
(3)
,
Julie Niemela
(2)
,
Isabelle Callebaut
(4)
,
Jennifer Stoddard
(2)
,
Christelle Lenoir
(5)
,
Vincent Barlogis
(6)
,
Catherine Farnarier
(7)
,
Frederic Vely
(8)
,
Nao Yoshida
(9)
,
Seiji Kojima
(10)
,
Hirokazu Kanegane
(11)
,
Akihiro Hoshino
(11)
,
Fabian Hauck
(12)
,
Ludovic Lhermitte
(13)
,
Vahid Asnafi
(14)
,
Philip Roehrs
(15)
,
Shaoying Chen
(16)
,
James Verbsky
(16)
,
Katherine Calvo
(17)
,
Ammar Husami
(18)
,
Kejian Zhang
(18)
,
Joseph Roberts
,
David Amrol
(19)
,
John Sleaseman
(20)
,
Amy Hsu
(21)
,
Steven Holland
(21)
,
Rebecca Marsh
(22)
,
Alain Fischer
(23, 24)
,
Thomas Fleisher
(25)
,
Capucine Picard
(26)
,
Sylvain Latour
(23)
,
Sergio Rosenzweig
(2)
1
Service d'Immunopathologie [Hôpital Saint-Louis, Paris]
2 Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland
3 Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm UMR 1163
4 IMPMC - Institut de minéralogie et de physique des milieux condensés
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM]
7 Service de Chirurgie
8 Service d'Immunologie [AP-HM]
9 Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya
10 Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya
11 Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo
12 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
13 Hôpital Necker - Enfants Malades [AP-HP]
14 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
15 Levine Children's Hospital, Carolinas Healthcare System, Charlotte, North Carolina
16 Department of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Madison, Wisconsin
17 Hematology section, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland
18 Division of Human Genetics and Division of Immune Deficiency and Bone Marrow Transplant, Cincinnati Children's Hospital, Cincinnati, Ohio
19 School of Medicine [University of South Carolina]
20 Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
21 Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland
22 Division of Human Genetics and Division of Immune Deficiency and Bone Marrow Transplant, Cincinnati Children's Hospital, Cincinnati
23 Developpement Normal et Pathologique du Système Immunitaire
24 Collège de France - Chaire Médecine expérimentale (A. Fischer)
25 Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland
26 Centre d'étude des Déficits Immunitaires
2 Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland
3 Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm UMR 1163
4 IMPMC - Institut de minéralogie et de physique des milieux condensés
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM]
7 Service de Chirurgie
8 Service d'Immunologie [AP-HM]
9 Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya
10 Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya
11 Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo
12 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
13 Hôpital Necker - Enfants Malades [AP-HP]
14 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
15 Levine Children's Hospital, Carolinas Healthcare System, Charlotte, North Carolina
16 Department of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Madison, Wisconsin
17 Hematology section, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland
18 Division of Human Genetics and Division of Immune Deficiency and Bone Marrow Transplant, Cincinnati Children's Hospital, Cincinnati, Ohio
19 School of Medicine [University of South Carolina]
20 Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
21 Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland
22 Division of Human Genetics and Division of Immune Deficiency and Bone Marrow Transplant, Cincinnati Children's Hospital, Cincinnati
23 Developpement Normal et Pathologique du Système Immunitaire
24 Collège de France - Chaire Médecine expérimentale (A. Fischer)
25 Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland
26 Centre d'étude des Déficits Immunitaires
Isabelle Callebaut
- Fonction : Auteur
- PersonId : 178738
- IdHAL : isabelle-callebaut
- ORCID : 0000-0003-3124-887X
- IdRef : 089078500
Vincent Barlogis
- Fonction : Auteur
- PersonId : 762453
- ORCID : 0000-0001-9645-3968
- IdRef : 108920046
Ludovic Lhermitte
- Fonction : Auteur
- PersonId : 771345
- ORCID : 0000-0003-2498-0376
Joseph Roberts
- Fonction : Auteur
Steven Holland
- Fonction : Auteur
- PersonId : 794556
- ORCID : 0000-0003-3207-5464
Alain Fischer
- Fonction : Auteur
- PersonId : 832560
Capucine Picard
- Fonction : Auteur
- PersonId : 758297
- ORCID : 0000-0001-8788-5056
- IdRef : 091572363
Sylvain Latour
- Fonction : Auteur
- PersonId : 764611
- ORCID : 0000-0001-8238-4391
- IdRef : 117717886
Résumé
Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.