Page 64 - Haematologica May 2022

Ferrata Storti Foundation
Haematologica 2022 Volume 107(5):1072-1085
Germline GATA2 variant disrupting endothelial eNOS function and angiogenesis can be restored by c-Jun/AP-1 upregulation
Giulio Purgatorio,1 Elisa Piselli,1 Giuseppe Guglielmini,1 Emanuela Falcinelli,1 Loredana Bury,1 Valeria Di Battista,2 Fabrizia Pellanera,2 Francesca Milano,2 Caterina Matteucci,2 Cristina Mecucci2# and Paolo Gresele1#
1Section of Internal and Cardiovascular Medicine, Department of Medicine and Surgery, University of Perugia and 2Hematology and Bone Marrow Transplantation Unit, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
#PG and CM contributed equally as co-senior authors.
ABSTRACT
GATA2 is a transcription factor with key roles in hematopoiesis. Germline GATA2 gene variants have been associated with sever- al inherited and acquired hematologic disorders, including myelodysplastic syndromes. Among the spectrum of GATA2 deficien- cy-associated manifestations thrombosis has been reported in 25% of patients, but the mechanisms are unknown. GATA2 was shown to be involved in endothelial nitric oxide synthase (eNOS) regulation and vas- cular development. We assessed eNOS expression and angiogenesis in patients with GATA2 deficiency. Platelets and blood outgrowth endothelial cells (BOEC) from GATA2 variant carriers showed impaired NO production and reduction of eNOS mRNA and protein expression and of eNOS activity. GATA2 binding to the eNOS gene was impaired in BOEC from GATA2-deficient patients, differently from control BOEC. GATA2 deficiency BOEC showed also defective angiogenesis, which was completely restored by treatment with the NO-donor S- nitroso-N-acetylpenicillamine (SNAP). Atorvastatin, but not resveratrol, largely restored eNOS expression, NO biosynthesis and neoangiogene- sis in GATA2-deficient BOEC by a mechanism involving increased expression of the eNOS transcription factor AP-1/c-JUN, replacing GATA2 when the latter is inactive. Our results unravel a possible throm- bogenic mechanism of GATA2 mutations, definitely establish the regu- lation of eNOS by GATA2 in endothelial cells and show that endothelial angiogenesis is strictly dependent on the eNOS/NO axis. Given the abil- ity of atorvastatin to restore NO production and angiogenesis by GATA2-deficient endothelial cells, the preventive effect of atorvastatin on thrombotic events and possibly on other clinical manifestations of the syndrome related to deranged angiogenesis should be explored in patients with GATA2 deficiency in an ad hoc designed clinical trial.
Introduction
GATA2 is a zinc finger transcription factor with key roles in the regulation of gene expression in hematopoietic cells.1 GATA2 binds consensus sequences in pro- moter/enhancer regions of target genes to regulate endothelial to hematopoietic transition in the embryo and to maintain the stem cell pool regulating hematopoi- etic stem cell (HSC) survival and self-renewal in the adult.2,3 Less than a decade ago heterozygous variants of GATA2 were first identified as the cause of four previous- ly described hematologic syndromes, later recognized as different manifestations of a single genetic disorder.4-7 Heterozygous germline variants in GATA2 lead to what is now referred to as GATA2 deficiency, a mutable disorder with remarkable clinical heterogeneity involving hematopoiesis, immunity and the lymphatic sys- tem.2,8 A number of non-hematological and non-infectious complications have also
Hemostasis
Correspondence:
PAOLO GRESELE
paolo.gresele@unipg.it
Received: February 1, 2021. Accepted: June 16, 2021. Pre-published: July 8, 2021.
https://doi.org/10.3324/haematol.2021.278450 ©2022 Ferrata Storti Foundation
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