Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

Abstract

Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of IKZF1 in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-α, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of IKZF1 mutation on immune function and the mechanism of immunomodulation by lenalidomide.

Human dendritic cell subsets: an update

“…Heterozygous GATA2 mutation and bi‐allelic IRF8 mutation abrogate pDC development in humans . Humans with an IKZF1 mutation have a selective pDC deficiency EcDC1 production …”

“… and ). IKZF1 deficiency in humans ablates pDC but results in an increase in cDC1 . IRF8 acts to preserve DC potential at several points in haematopoiesis by direct or indirect competition with a series of transcription factors that promote other lineages: (i) IRF8 limits CEBPA‐mediated granulocytic differentiation; (ii) with PU.1 it interacts with KLF4 to modulate the balance of DC to monocyte differentiation; (iii) it competes with IRF4 to control cDC1:cDC2 output and; (iv) a BATF3 ‘switch’ ensures that unopposed IRF8 maintains cDC1 maturation .…”

“…61,62 Humans with an IKZF1 mutation have a selective pDC deficiency EcDC1 production. 63 A key axis in regulating the balance of pDC and myeloid cDC development is the antagonism between ID2, an inhibitor of DNA binding, and E2-2, a basic hemophagocytic lymphohistiocytosis protein. 58,60 E2-2 is a lineage-determining factor for pDC that is negatively regulated by ID2.…”

Whole‐genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm

“…HNRNPK encodes a nuclear ribonucleoprotein that influences multiple cellular functions (eg, cell cycle, chromatin remodeling, RNA synthesis, and processing) in hematopoietic cells . IKZF1 , on the other hand, encodes a transcription factor with critical roles in the development of various hematopoietic lineages, including pDCs . Remarkably, deletions at 7p12.2 were considerably narrow (<500 Kb) in four of seven affected patients, ranging from loss of IKZF1 and a few neighboring genes, to loss of the IKZF1 locus exclusively, to loss of IKZF1 's exon 8 only (Figure A,B).…”

“…on the other hand, encodes a transcription factor with critical roles in the development of various hematopoietic lineages, including pDCs. [28][29][30][31] Remarkably, deletions at 7p12.2 were considerably narrow (<500 Kb) in four of seven affected patients, ranging from loss of IKZF1 and a few neighboring genes, to loss of the IKZF1 locus exclusively, to loss of IKZF1's exon 8 only ( Figure 5A,B). Patients where deletions did not involve the whole locus, but part of it, enclosed exons encoding IKZF1's functional domains ( Figure 5B).…”