GATA2

Primary Author(s)*

Kay Weng Choy MBBS

Synonyms

GATA Binding Protein 2, IMD21, NFE1B, DCML (dendritic cell, monocyte, and lymphoid deficiency), MONOMAC (Monocytopenia and Mycobacterium avium complex infections)

Genomic Location

Cytoband: 3q21.3

Genomic Coordinates:

chr3:128,479,422-128,493,187 (GRCh38/hg38) chr3:128,198,265-128,212,030 (GRCh37/hg19)

Cancer Category/Type

Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), chronic myeloid leukemia (CML) Non-small cell lung cancer (NSCLC)

Gene Overview

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]. 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].

MDS/AML

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].

CML

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].

Non-small cell lung cancer (NSCLC)

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

GATA2 mutations include amino acid substitutions, insertion and deletions, and frameshifts scattered throughout the gene but predominantly found in the region encoding the two zinc finger domains [1]. Approximately 100 GATA2 mutations have been described, either as germline genetic defects or somatic mutations in association with other drivers, such as biallelic CEBPA mutation in AML [1].

• About one-third of all germline mutations are inherited and the rest occur de novo; these include a small number of whole gene deletions and 29 frameshift or nonsense mutations, distributed from the initiation site to the end of the second zinc finger

• A further 11 in-frame insertions or deletions and 54 single nucleotide variants causing amino acid substitution are predominantly found in exons 3, 4 and 5, encoding the two zinc finger domains

• Splice site mutations are also found between coding exons 3 and 4

• Two discrete mutations of the intron 5 enhancer, predicted to affect transcription factor binding, have also been reported

• Overall, approximately two-thirds of all cases described have mutations in the zinc finger domains

• No mutations have been observed in the 5’ or 3’ untranslated regions (UTRs) or in the distal section of the last exon, beyond the region encoding the second zinc finger

• Many single amino acid substitutions are predicted to significantly impair DNA binding of the zinc fingers potentially making them functionally inactive. It is also possible that these variants have residual function or can even act in a dominant negative fashion

• Although more than half the variants described are single amino acid substitutions that may lead to the translation of mutated protein with altered function, it is proposed that the functional effects of heterozygous mutations are primarily due to haploinsufficiency

According to the Catalogue of Somatic Mutations in Cancer (COSMIC), c.490G>A (NM_032638.4) (p.Ala164Thr) and c.15C>G (NM_032638.4) (p.Pro5Pro) have been observed in 49 and 96 cases, respectively, predominantly in the setting of acute myeloid leukemia (https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=GATA2, Accessed 1st August 2018)

Copy Number Loss	Copy Number Gain	LOH	Loss-of-Function Mutation	Gain-of-Function Mutation	Translocation/Fusion

Internal Pages

Acute Myeloid Leukemia (AML) with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2);GATA2, MECOM

References

EXAMPLE Book

1. Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

EXAMPLE Journal Article

1. Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.

Notes

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