Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency
David Boutboul, … , Sylvain Latour, Sergio D. Rosenzweig
David Boutboul, … , Sylvain Latour, Sergio D. Rosenzweig
Published June 11, 2018
Citation Information: J Clin Invest. 2018;128(7):3071-3087. https://doi.org/10.1172/JCI98164.
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Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency

Abstract

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.

Authors

David Boutboul, Hye Sun Kuehn, Zoé Van de Wyngaert, Julie E. Niemela, Isabelle Callebaut, Jennifer Stoddard, Christelle Lenoir, Vincent Barlogis, Catherine Farnarier, Frédéric Vely, Nao Yoshida, Seiji Kojima, Hirokazu Kanegane, Akihiro Hoshino, Fabian Hauck, Ludovic Lhermitte, Vahid Asnafi, Philip Roehrs, Shaoying Chen, James W. Verbsky, Katherine R. Calvo, Ammar Husami, Kejian Zhang, Joseph Roberts, David Amrol, John Sleaseman, Amy P. Hsu, Steven M. Holland, Rebecca Marsh, Alain Fischer, Thomas A. Fleisher, Capucine Picard, Sylvain Latour, Sergio D. Rosenzweig

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Figure 4

Myeloid abnormalities associated with heterozygous IKZF1N159S/T mutations.

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Myeloid abnormalities associated with heterozygous IKZF1N159S/T mutation...
(A) PBMCs from G1 and a healthy donor control (Ctrl) were analyzed for the presence of DCs. Dot plots (left panels) of lineage-negative (CD3–, CD19–, and CD56–), HLA-DR–positive, and CD14– or CD16– negative population corresponding to DCs. The CD11c and CD303 markers enabled the delineation of mDCs (CD11c+CD303–) and pDCs (CD11c–CD303+). Right panels show the results expressed as percentage of PBMCs from patients B1, G1, and 5 healthy donor controls. (B) PBMCs from C1, D1, and G1 and healthy donor controls (Ctrl) were stimulated with the indicated TLR agonist for 24 hours. Cell-free supernatants were harvested, and cytokines (IL-6, IL-1β, TNF-α) were measured with the Luminex 200 System. Data are from one experiment performed in patients C1, D1, and G1 and compared with 4 healthy donor controls (mean ± SD). (C) PBMCs from C1 and D1 were stimulated with (blue line) or without (solid red) soluble anti-CD3 and anti-CD28 antibodies (1 μg/ml each) in the presence or absence of the healthy donor’s monocytes or B cells for 5 days. The proliferation was determined by dilution of CellTrace Violet dye analyzed by flow cytometry. Data are representative of 3 experiments.