Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles

Abstract

IKZF1 encodes Ikaros, a zinc finger–containing transcription factor crucial to the development of the hematopoietic system. Germline pathogenic variants in IKZF1 have been reported in patients with acute lymphocytic leukemia and immunodeficiency syndromes. Diamond–Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid hypoplasia, associated with a spectrum of congenital anomalies and an elevated risk of certain cancers. DBA is usually caused by heterozygous pathogenic variants in genes that function in ribosomal biogenesis; however, in many cases the genetic etiology is unknown. We identified a germline IKZF1 variant, rs757907717 C > T, in identical twins with DBA-like features and autoimmune gastrointestinal disease. rs757907717 C > T results in a p.R381C amino acid change in the IKZF1 Ik-x isoform (p.R423C on isoform Ik-1), which we show is associated with altered global gene expression and perturbation of transcriptional networks involved in hematopoietic system development. These data suggest that this missense substitution caused a DBA-like syndrome in this family because of alterations in hematopoiesis, including dysregulation of networks essential for normal erythropoiesis and the immune system.

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

“…Somatic IKZF1 genetic aberrations have adverse effects on clinical outcomes (overall survival and relapse-free survival) and several molecular mechanisms have been implicated as the mode of IKAROS deficiency in both autoimmune deficiency syndromes and HM manifestation ( 108 , 109 ). These include missense variants at DNA contact residues that are still able to dimerize with wildtype IKAROS but are unable to bind target DNA ( 103 , 110 ), haploinsufficiency with deletion of one IKZF1 allele ( 103 ), differential expression in gene networks involved in cancer, cell signaling, apoptosis, and hematopoiesis ( 111 ) and transcription, dimerization, subcellular localization, and cell adhesion LOF ( 107 , 108 ). Interestingly, somatic mutations in IKZF1 are recurrently detected in IKZF1 germline carriers with B-cell precursor ALL, suggesting that cells carrying the germline variant favor acquisition of a second (i.e., biallelic) IZKF1 transforming event ( 112 ).…”

The Diverse Genomic Landscape of Diamond–Blackfan Anemia: Two Novel Variants and a Mini-Review

“…Unlike DBA, the latter entity can be effectively treated with EPO supplementation [3,31]. In the same context, the IKZF1 R381C variant was reported to have DBA-like features, an immune-related gastrointestinal phenotype, and an alteration in hematopoietic gene expression networks, while mutations in the MPL proto-oncogene of the thrombopoietin (TPO) receptor have been linked to elevated TPO and a DBA-like phenotype [14,32]. Loss-of-function variants in the MYSM1 gene, which is a regulator of transcription, present with transfusion-dependent refractory anemia in early childhood in addition to mild thrombocytopenia and low NK-and B-cell counts.…”