IKAROS is a transcription factor that is well known to be critical for lymphocyte differentiation. 1, 2 IKZF1 codes for the IKAROS zinc finger DNA-binding protein that regulates target gene expression through interactions with chromatin remodeling complexes. IKAROS binds to the regulatory regions of target genes, resulting in their recruitment into pericentromeric heterochromatin (PC-HC), which leads to their activation or repression. 3, 4 Several types of Ikaros deficiencies in mice have been reported to cause various immunodeficiencies and subsequent T-cell leukemia. 1, 4–7 Among these previously reported models, heterozygous Ikaros-Plastic mice harboring a point mutation within a zinc finger of the N-terminal DNA-binding domain have shown B-cell and natural killer (NK)-cell deficiencies as well as impaired T-cell differentiation. 4 In addition, these mice develop splenomegaly as a result of thymocyte proliferation within the spleen at a pre-leukemic phase and have a high incidence of late development of T-cell leukemia, which is frequently accompanied by the acquisition of a somatic Notch1 mutation. 8 In humans, a germline mutation in IKZF1 was originally identified in an infant with pancytopenia and loss of B cells. 9 More recently, 29 additional cases of germline IKZF1 mutations with the loss of B cells have been reported, and two of these cases progressed to B-cell leukemia. 10 However, the clinical presentations in these patients were inconsistent with those in reported reference mice with regard to T-cell defects and leukemic phenotypes. Here we report the first case of a patient with severe immunodeficiency that later progressed to T-cell acute lymphoblastic leukemia (T-ALL) caused by a germline IKZF1 mutation associated with a somatic NOTCH1 mutation, which reflects the condition of heterozygous Ikaros-Plastic mice. A female patient presented with severe pulmonary infection complicated by acute respiratory distress syndrome at the age of 9 months. Her immunological evaluation showed profound lymphopenia and hypogammaglobulinemia, with a nearly absence of B cells and a low number of T cells (Supplementary Table S1). T-cell proliferation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) was markedly reduced. Subsequent to a diagnosis of primary combined immunodeficiency, she promptly underwent purified CD34-positive bone marrow transplantation from her haploidentical mother without preconditioning at 10 months of age. Although the grafts were rejected with complete recipient chimerism and hypogammaglobulinemia, along with sustained nearly loss of B cells, her own T cells spontaneously recovered, and almost normal proliferation of T cells was observed on stimulation with PHA or Con-A. The level of NK cells was reduced, and impaired cytotoxic activity of NK cells was observed. She subsequently presented with neutropenia and was given occasional G-CSF, antibiotics and antifungal treatment, in addition to monthly intravenous immunoglobulin. Over the next several years, she had protracted diarrhea, severe pneumocystis pneumonia and recurrent episodes of oral infections with Candida albicans. Massive splenomegaly was apparent at 10 years of age (Supplementary Figure S1), and she developed T-ALL at 13 years of age. Her white blood cell count was 385 700/μl, with 98% of lymphoblasts. With regard to the leukemic phenotype, leukemias in heterozygous Ikaros-Plastic mice are generally of a CD8+CD4+(double positive, DP) or CD8+CD4int T-cell phenotype because of differentiation arrest at the DP stage, which is caused by defective Ikaros function that results in impairment in the …