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Guanine-adenine-thymine-adenine 2 (GATA2) is one of six GATA binding-factors that regulate gene expression by binding to the DNA motif GATA motifs in the human genome and other transcription factors via two zinc finger domains (ZF1 and ZF2) [1]. During embryogenesis, GATA2 plays an important role in the endothelial to hematopoietic transition that produces the first adult hematopoietic stem cells (HSCs) [2]. In adult hematopoiesis, it is an important transcriptional regulator of hematopoiesis required for HSCs survival and self-renewal [3,4,5]. GATA2 interacts with a complex network of transcription factors that determine early lineage commitment, including SPI1 (PU.1), FLI1, TAL1 (SCL), LMO2 and RUNX1 [3,4,5]. During hematopoietic differentiation, GATA2 is presumed to play a key role in downstream fate decisions together with CEBPA, GATA1 and SPI1, and is essential for monocytic, granulocytic, and lymphoid differentiation (figure 1) [1]. Antagonism between pairs of transcription factors is a key feature of fate decisions, an example being GATA2 and SPI1 (PU.1) in influencing the spectrum of early commitment [1].  

Guanine-adenine-thymine-adenine 2 (GATA2) is one of six GATA binding-factors that regulate gene expression by binding to the DNA motif GATA motifs in the human genome and other transcription factors via two zinc finger domains (ZF1 and ZF2) [1]. During embryogenesis, GATA2 plays an important role in the endothelial to hematopoietic transition that produces the first adult hematopoietic stem cells (HSCs) [2]. In adult hematopoiesis, it is an important transcriptional regulator of hematopoiesis required for HSCs survival and self-renewal [3,4,5]. GATA2 interacts with a complex network of transcription factors that determine early lineage commitment, including SPI1 (PU.1), FLI1, TAL1 (SCL), LMO2 and RUNX1 [3,4,5]. During hematopoietic differentiation, GATA2 is presumed to play a key role in downstream fate decisions together with CEBPA, GATA1 and SPI1, and is essential for monocytic, granulocytic, and lymphoid differentiation (figure 1) [1]. Antagonism between pairs of transcription factors is a key feature of fate decisions, an example being GATA2 and SPI1 (PU.1) in influencing the spectrum of early commitment [1].  

Three GATA2 transcripts have been described [1]. Two transcripts (NM_001145661.1 and NM_032638.4) encode the same isoform 1 (480 residues) [1]. A third transcript (NM_001145662.1) encodes a shorter isoform 2 which is truncated by 14 residues at the second zinc finger, as a result of alternative splicing of the last exon [1]. Expression of the distal first exon (IS) is restricted to hematopoiesis and is involved in specification of definitive HSCs during embryogenesis [1].

Three GATA2 transcripts have been described [1]. Two transcripts (NM_001145661.1 and NM_032638.4) encode the same isoform 1 (480 residues) [1]. A third transcript (NM_001145662.1) encodes a shorter isoform 2 which is truncated by 14 residues at the second zinc finger, as a result of alternative splicing of the last exon [1]. Expression of the distal first exon (IS) is restricted to hematopoiesis and is involved in specification of definitive HSCs during embryogenesis [1].

GATA2 mutated disorders include MonoMac syndrome (Monocytopenia and Mycobacterium avium complex infections), congenital neutropenia, congenital lymphedema (Emberger’s syndrome), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia), sensorineural defects, viral warts, and a spectrum of aggressive infections seen across all age groups [2].  

GATA2 mutated disorders include MonoMac syndrome (Monocytopenia and Mycobacterium avium complex infections), congenital neutropenia, congenital lymphedema (Emberger’s syndrome), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia), sensorineural defects, viral warts, and a spectrum of aggressive infections seen across all age groups [2].

GATA2 overexpression has been reported in up to half of non-familial AML and correlates with poor prognosis with shorter overall and event-free survival when treated with standard chemotherapy [6,7]. Bone marrow biopsies are frequently hypocellular in contrast to the common MDS marrow picture, with abundant atypical megakaryocytes in >90% of patients [8].

AML with inv(3)(q21;3q26.2)/t(3;3)(q21.3;q26.2) accounts for 1-2% of all AML [9]. It is an aggressive disease with short survival [9]. It is associated with aberrant expression of the stem-cell regulator EVI1 [9]. Both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, identified as the cause of sporadic familial AML/MDS (and MonoMac/Emberger syndromes) [9].

 

GATA2 mutation Leu359Val (NM_001145661.1:c.1075T>G) gain-of-function has been found in approximately 10% of patients with accelerated or blast phase CML but not chronic lymphocytic leukemia (CLL) or acute lymphoblastic leukemia (ALL) [10,11]. This is thought to be mediated through PU.1 inhibition [2]. While GATA2 overexpression has been associated with AML, and Leu359Val gain-of-function mutation with CML, loss-of-function mutations of GATA2 such as Thr354Met (NM_001145661.1:c.1061C>T) have been linked to MDS [2]. Leu359 and Thr354 are located in the same region on the second zinc finger of GATA2, highlighting the influence of GATA2 in myeloid precursors [2].

The GATA2 transcriptional network is a requisite for RAS oncogene-driven NSCLC [12]. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected [12]. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development [12]. Furthermore, Gata2 deletion in established Kras-mutant tumors has been found to induce significant regression [12].

==Common Alteration Types==

==Common Alteration Types==