Quantitative and qualitative impairments in GATA2 and myeloid neoplasms

Abstract

GATA2 is a key transcription factor critical for hematopoietic cell development.During the past decade, it became clear that heterozygous germline mutations in the GATA2 gene cause bone marrow failure and primary immunodeficiency syndrome, conditions that lead to a predisposition toward myeloid neoplasms, such as myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Somatic mutations of the GATA2 gene are also involved in the pathogenesis of myeloid malignancies. Cases with GATA2 gene mutations are divided into two groups, resulting in either a quantitative deficiency or a qualitative defect in the GATA2 protein depending on the mutation position and type. In the former case, GATA2 mRNA expression from the mutant allele is markedly reduced or completely abrogated, and reduced GATA2 protein expression is involved in the pathogenesis. In the latter case, almost equal amounts of structurally abnormal and wildtype GATA2 proteins are predicted to be present and contribute to the pathogenesis. The development of mouse models of these human GATA2-related diseases has been undertaken, which naturally develop myeloid neoplasms. K E Y W O R D S disease model mice, familial MDS/AML, GATA2, quantitative or qualitative change

Gata2 heterozygous mutant mice exhibit reduced inflammatory responses and impaired bacterial clearance

“…One of the major clinical manifestations of syndromic GATA2 haploinsufficiency is primary immunodeficiency with marked susceptibility to weakly virulent bacterial, viral, and fungal infections, suggesting that GATA2 haploinsufficiency compromises the innate immune system of the host ( Jung et al., 2020 ; Shimizu and Yamamoto, 2020 ). However, immunological insights and molecular explanations for GATA2-haploinsufficient patients are largely lacking.…”

“…Many mechanistic aspects of the host immune defense system and its failures in the face of these recurrent challenges have long been topics of debate ( Ibrahim et al., 2017 ). Clinical and genetic studies conducted over the last decade have revealed the inextricable link between the hematopoietic transcription factor GATA2 and the etiology of primary immunodeficiency disorder ( Jung et al., 2020 ; Shimizu and Yamamoto, 2020 ).…”

“…Thus, haploinsufficiency of GATA2 underlies the pathogenesis of these conditions. Monoallelic complete gene deletion, mutations in the fifth intron cis -regulatory elements, and variations within the 5′ noncoding exons of GATA2 have also been found in diseased patients ( Bresnick et al., 2020 ; Collin et al., 2015 ; Hsu et al., 2013 ; Johnson et al., 2012 ; Shimizu and Yamamoto, 2020 ). This spectrum of qualitative and quantitative mutations of GATA2 is believed to compromise the regulatory network of the hematopoietic system and the host defense system.…”

Tumor suppressing role of serum-derived exosomal microRNA-15a in osteosarcoma cells through the GATA binding protein 2/murine double minute 2 axis and the p53 signaling pathway

“…GATA2 is an essential factor for hematopoietic cell development, and its aberrant activation has been demonstrated in human malignancies [15][16][17]. This study speculated that the abnormal expression of GATA2 was possibly associated with OS development.…”

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

“…Like RUNX1, GATA2 is crucial for the production and maintenance of HSCs in embryonic and adult hematopoiesis and HSCs are very sensitive to the GATA2 levels [108]. As a consequence, qualitative or quantitative mutations impairing GATA2 expression are recurrent in several hematopoietic diseases, including MDS and AML [109]. One of the better-described examples of a "regulatory" mutation affecting the level of a TF in AML is the 3q21;q26 inversion.…”