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Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):260-267
Dysregulation of oncogenic factors by GFI1B p32: investigation of a novel GFI1B germline mutation
Michela Faleschini,1 Nicole Papa,1 Marie-Christine Morel-Kopp,2 Caterina Marconi,3 Tania Giangregorio,1 Federica Melazzini,4 Valeria Bozzi,4 Marco Seri,3 Patrizia Noris,4 Alessandro Pecci,4 Anna Savoia1,5 and Roberta Bottega1
1Institute for Maternal and Child Health – IRCCS Burlo Garofolo, Trieste, Italy; 2Department of Hematology and Transfusion Medicine, Royal North Shore Hospital and Northern Blood Research Center, Kolling Institute, University of Sydney, Sydney, New South Wales, Australia; 3Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 4Biotechnology Research Laboratories, IRCCS Policlinico San Matteo Foundation, Pavia, Italy and 5Department of Medical Sciences, University of Trieste, Trieste, Italy
ABSTRACT
GFI1B is a transcription factor essential for the regulation of ery- thropoiesis and megakaryopoiesis, and pathogenic variants have been associated with thrombocytopenia and bleeding. Analysing thrombocytopenic families by whole exome sequencing, we identified a novel GFI1B variant (c.648+5G>A), which causes exon 9 skipping and overexpression of a shorter p32 isoform. We report the clinical data of our patients and critically review the phenotype observed in individuals with different GFI1B variants leading to the same effect on the p32 expression. Since p32 is increased in acute and chronic leukemia cells, we tested the expression level of genes playing a role in various type of cancers, including hematological tumors and found that they are significantly dysregulated, suggesting a potential role for GFI1B in carcinogenesis regulation. Increasing the detection of individuals with GFI1B variants will allow us to better characterize this rare disease and determine whether it is associated with an increased risk of developing malignancies.
Introduction
Inherited thrombocytopenias represent a group of heterogeneous rare disorders characterized by a reduced platelet count that may associate with other defects.1 Mutations in at least 40 different genes are responsible for these disorders, including a recently discovered autosomal dominant condition reported as GFI1B-associated bleeding disorder or platelet-type bleeding disorder 17 (OMIM 187900), which is caused by pathogenic variants of the GFI1B (growth factor-independent 1B) gene.2–4
GFI1B is a transcription repressor of the GFI zinc-finger family, consisting of three domains: a highly conserved N-terminal repressor domain called Snail/Gfi1, which recruits chromatin regulatory proteins; an intermediary domain of unknown func- tion; and a C-terminal cluster of six zinc-finger domains (ZNF), of which ZNF 3, 4, and 5 bind to DNA, while ZNF 1,2, and 6 have yet to be characterized.5,6 GFI1B plays a key role in hematopoiesis through different isoforms. Indeed, in addition to gener- ating a long isoform consisting of 330 amino acids (p37), GFI1B mRNA undergoes an alternative splicing process producing a short isoform of 284 residues (p32) charac- terized by the skipping of exon 9 (NG_034227) and consequent removal of ZNF 1 and 2. The long p37 form is reported to have a pivotal role in megakaryopoiesis and platelet production, whereas the short p32 form is essential for erythroid lineage.7
GFI1B regulates the differentiation of the hematopoietic stem cells through the repression of different promoters, including its self-regulatory regions via an autoreg- ulatory feedback mechanism.7–9 Among other targets is the hematopoietic stem cell marker CD34, whose downregulation during hematopoiesis is not quenched when GFI1B is mutated. Therefore, one feature of the GFI1B-associated bleeding disorder is the aberrant expression of CD34 on patients' platelets, which is due to the dysreg-
Platelet Biology & its Disorders
Correspondence:
ANNA SAVOIA
anna.savoia@burlo.trieste.it
Received: July 31, 2020. Accepted: December 21, 2020. Pre-published: January 21, 2021.
https://doi.org/10.3324/haematol.2020.267328 ©2022 Ferrata Storti Foundation
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