Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations

• Published in: Journal of allergy and clinical immunology Vol. 140; no. 1; pp. 223 - 231
• Main Authors: Hoshino, Akihiro, Okada, Satoshi, Yoshida, Kenichi, Nishida, Naonori, Okuno, Yusuke, Ueno, Hiroo, Yamashita, Motoi, Okano, Tsubasa, Tsumura, Miyuki, Nishimura, Shiho, Sakata, Sonoko, Kobayashi, Masao, Nakamura, Haruna, Kamizono, Junji, Mitsui-Sekinaka, Kanako, Ichimura, Takuya, Ohga, Shouichi, Nakazawa, Yozo, Takagi, Masatoshi, Imai, Kohsuke, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Miyano, Satoru, Ogawa, Seishi, Kojima, Seiji, Nonoyama, Shigeaki, Morio, Tomohiro, Kanegane, Hirokazu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2017; Elsevier Limited
• Subjects: Acute lymphoblastic leukemia; Adolescent; Adult; Age; Allergy and Immunology; autoimmune disease; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmunity; B-cell deficiency; B-Lymphocytes - immunology; Bone marrow; Cell cycle; Child; common lymphoid progenitor; Deoxyribonucleic acid; DNA; DNA binding; dysgammaglobulinemia; Female; Flow cytometry; Genomes; Germ-Line Mutation; germline mutation; Hematologic Diseases - genetics; Hematologic Diseases - immunology; Hematopoiesis - genetics; Hemopoiesis; Humans; Ikaros; Ikaros protein; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - immunology; IKZF1; Immunodeficiency; Immunoglobulin A; Kinases; Leukemia; Localization; Lymphocyte Count; Lymphocytes B; Lymphopoiesis; Male; Mutation; nuclear localization; Nucleotide sequence; Pancytopenia; Pediatrics; Plasmids; Purpura; Stem cells; Systemic lupus erythematosus; T-Lymphocytes - immunology; Thrombocytopenic purpura; Transcription factors; Vasculitis; Young Adult; LMPP; ITP; WES; common lymphoid progenitor; CLP; dysgammaglobulinemia; CMP; B-cell deficiency; IKZF1; GMP; ZF; autoimmune disease; germline mutation; SLE; DNA binding; BCP-ALL; Acute lymphoblastic leukemia; Ikaros; EMSA; nuclear localization; Ph; HSC; HSCT; WT; Common myeloid progenitor; Lymphoid-primed multipotent progenitor; Systemic lupus erythematosus; Philadelphia positive; Zinc finger; Granulomonocyte progenitor; Hematopoietic stem cell transplantation; B-cell precursor acute lymphoblastic leukemia; Whole-exome sequencing; Wild-type; Hematopoietic stem cell; Immune thrombocytopenic purpura; Electrophoresis mobility shift assay
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.09.029

Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described. We sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations. We performed whole-exome sequencing in patients from a dysgammaglobulinemia or autoimmune disease cohort and used a candidate gene approach in 4 patients. Functional and laboratory studies, including detailed lymphopoiesis/hematopoiesis analysis in the bone marrow, were performed. Nine patients from 6 unrelated families were identified to have heterozygous germline mutations in IKZF1. Age of onset was 0 to 20 years (mean, 7.4 years). Eight of 9 patients presented with dysgammaglobulinemia accompanied by B-cell deficiency. Four of 9 patients had autoimmune disease, including immune thrombocytopenic purpura, IgA vasculitis, and systemic lupus erythematosus. Nonautoimmune pancytopenia was observed in 1 patient. All of the mutant Ikaros protein demonstrated impaired DNA binding to the target sequence and abnormal diffuse nuclear localization. Flow cytometric analysis of bone marrow revealed reduced levels of common lymphoid progenitors and normal development of pro-B to pre-B cells. Germline heterozygous IKZF1 mutations cause dysgammaglobulinemia; hematologic abnormalities, including B-cell defect; and autoimmune diseases.