Normal hematologic parameters and fetal hemoglobin silencing with heterozygous IKZF1 mutations

N Abdulhay, C Fiorini, A Kumánovics… - Blood, The Journal …, 2016 - ashpublications.org
N Abdulhay, C Fiorini, A Kumánovics, AA Sun, J Hansen-Rejali, KV Voelkerding…
Blood, The Journal of the American Society of Hematology, 2016ashpublications.org
The multiple zinc finger-containing transcription factor, IKAROS/IKZF1, has multifaceted
roles in hematopoiesis. 1 Numerous studies using both human primary hematopoietic cells
and mouse models have suggested that IKZF1 plays a key role in erythropoiesis and the
fetalto-adult hemoglobin (Hb) switch. 2-7 Even with partial suppression of IKZF1, fetal Hb
(HbF) silencing appeared to be impaired in these model systems. 4, 7 In addition, extensive
studies of various mouse models have demonstrated that Ikzf1 is necessary for …
The multiple zinc finger-containing transcription factor, IKAROS/IKZF1, has multifaceted roles in hematopoiesis. 1 Numerous studies using both human primary hematopoietic cells and mouse models have suggested that IKZF1 plays a key role in erythropoiesis and the fetalto-adult hemoglobin (Hb) switch. 2-7 Even with partial suppression of IKZF1, fetal Hb (HbF) silencing appeared to be impaired in these model systems. 4, 7 In addition, extensive studies of various mouse models have demonstrated that Ikzf1 is necessary for hematopoietic stem cell (HSC) maintenance, lymphoid-priming in early multipotential hematopoietic progenitors, B-and T-lymphopoiesis, and suppression of specific myeloid lineages. Ikzf1 knockout mice have a 30-to 40-fold reduction in HSCs, an absence of all B-and T-lymphoid precursors, and an increase in the number of myeloid precursors, including those giving rise to megakaryocytes, basophils, and neutrophils. 1, 8-10 Ongoing work is focused on understanding the mechanisms through which IKZF1 is able to mediate these various activities during hematopoiesis through association with chromatin regulatory complexes. 1, 11 However, recent findings have also highlighted key differences in aspects of hematopoiesis observed in humans compared with various model systems. 12-15 Importantly, a study in primary human hematopoietic cells has shown that suppression of IKZF1 does not alter HbF silencing and has little effect on erythropoiesis, 16 in contrast with other earlier studies. 4, 7 Thus, analysis of human IKZF1 mutations in vivo would enhance our understanding of this gene, s function, similar to the manner in which other human genetic studies have provided key insights into hematopoiesis and Hb gene regulation. 15, 17-21 For example, haploinsufficiency of the multiple zinc finger-containing transcription factor BCL11A in humans is sufficient to allow highlevel persistence of HbF, validating this factor as a key therapeutic target for HbF induction to treat patients with sickle cell disease (SCD) and b-thalassemia. 17, 18, 22-24
Recently, an autosomal dominant form of a common variable immunodeficiency (CVID)-like syndrome with progressive B lymphopenia and an increased risk of hematologic malignancies was associated with heterozygous loss-of-function mutations in IKZF1. 25 Despite an extensive analysis of immunologic parameters in these individuals, hematologic phenotypes were not obviously apparent or described. We therefore performed hematologic analyses (including complete blood counts [CBCs], white blood cell [WBC] subset assessments, and Hb subtype quantification) on a total of 16 affected individuals carrying IKZF1 mutations and 11 unaffected family members from 2 separate pedigrees (Table 1; Figure 1). Approval for this study was obtained from the Institutional Review Boards at the National Institutes of Health, the University of Utah, and Boston Children, s Hospital. Informed consent for this study was provided according to the Declaration of Helsinki. Family C has a c. 500A. G
ashpublications.org