Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations Akihiro Hoshino, MD, PhD, Satoshi Okada, MD, PhD, Kenichi Yoshida,

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Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations Akihiro Hoshino, MD, PhD, Satoshi Okada, MD, PhD, Kenichi Yoshida, MD, PhD, Naonori Nishida, MD, PhD, Yusuke Okuno, MD, PhD, Hiroo Ueno, MD, Motoi Yamashita, MD, Tsubasa Okano, MD, Miyuki Tsumura, PhD, Shiho Nishimura, MD, Sonoko Sakata, MD, Masao Kobayashi, MD, PhD, Haruna Nakamura, MD, Junji Kamizono, MD, PhD, Kanako Mitsui-Sekinaka, MD, Takuya Ichimura, MD, Shouichi Ohga, MD, PhD, Yozo Nakazawa, MD, PhD, Masatoshi Takagi, MD, PhD, Kohsuke Imai, MD, PhD, Yuichi Shiraishi, MD, PhD, Kenichi Chiba, BA, Hiroko Tanaka, BS, Satoru Miyano, PhD, Seishi Ogawa, MD, PhD, Seiji Kojima, MD, PhD, Shigeaki Nonoyama, MD, PhD, Tomohiro Morio, MD, PhD, Hirokazu Kanegane, MD, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 1, Pages 223-231 (July 2017) DOI: 10.1016/j.jaci.2016.09.029 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Heterozygous germline IKZF1 mutations can cause hematopoietic abnormality and autoimmunity. A, Pedigrees of families A to F. Squares and circles indicate male and female subjects, respectively. B, Schematic of Ikaros. Black boxes labelled by number indicate ZF domains. Journal of Allergy and Clinical Immunology 2017 140, 223-231DOI: (10.1016/j.jaci.2016.09.029) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Genetic analysis of heterozygous mutation in IKZF1. A, ZF2 and ZF4 sequences. Cysteine (C) and histidine (H) residues, which coordinate the zinc atom, are highlighted in red. The −1, 2, 3, and 6 positions, which are the DNA-interacting residues, are highlighted in blue. The −12, −3, and 4 positions, which are essential residues for structural integrity, are highlighted in yellow. B, Crystal structures of IKZF1 (yellow). C147, N159, and R162 are shown in red. Journal of Allergy and Clinical Immunology 2017 140, 223-231DOI: (10.1016/j.jaci.2016.09.029) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Splicing variants in patient E.II.1. A, Schematic representation of the alleles obtained by direct cloning and their numbers. B, Insertions, deletions, or both. C, Ikaros protein expression in nonstimulated PBMCs. Journal of Allergy and Clinical Immunology 2017 140, 223-231DOI: (10.1016/j.jaci.2016.09.029) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Functional analysis of Ikaros mutants. A, Immunoblot. Upper and lower panels indicate anti-Ikaros and anti–β-actin, respectively. Ikaros mutants are shown to be normal at 63 kDa. B, EMSA. Ikaros mutants (C147R, N159S, R162Q, and R162W) completely abolish DNA binding to the IK-bs4 sequence, whereas the Y210C mutant shows weak residual binding. Arrows indicate Ikaros-containing complexes. C, Subcellular localization of Ikaros protein in NIH3T3 cells expressing HA-tagged WT or mutant Ikaros. D, Subcellular localization of Ikaros protein in NIH3T3 cells expressing V5-tagged WT Ikaros. E, Subcellular localization of Ikaros protein in NIH3T3 cells coexpressing HA-tagged WT or mutant Ikaros and V5-tagged WT Ikaros. Journal of Allergy and Clinical Immunology 2017 140, 223-231DOI: (10.1016/j.jaci.2016.09.029) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Immunologic studies of patients with IKZF1 mutations. A, B-cell counts in lymphocytes. Ctrl, Control subjects; Pt, patients. B, Sequential changes of serum IgG levels before starting immunoglobulin replacement therapy. Dotted lines indicate upper and lower healthy control values. C, B-cell subsets. Circles indicate CD10+CD38+ or CD24+CD38+ transitional B cells. Journal of Allergy and Clinical Immunology 2017 140, 223-231DOI: (10.1016/j.jaci.2016.09.029) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Sequential change of laboratory data in patient F.2. A, Course of B-cell counts. B, Sequential changes of red blood cell and platelet counts. Journal of Allergy and Clinical Immunology 2017 140, 223-231DOI: (10.1016/j.jaci.2016.09.029) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Hematopoietic cell and B-cell development in bone marrow. A, Evaluation of hematopoiesis and B-cell development in bone marrow by using multicolor flow cytometry. B, Comparison of each component in hematopoiesis and B-cell development in bone marrow. White bars indicate means ± SDs of the control subjects (HSCs and progenitors, n = 4; B lineage, n = 10). Journal of Allergy and Clinical Immunology 2017 140, 223-231DOI: (10.1016/j.jaci.2016.09.029) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions