Overexpression of the GATA2 transcription factor that is not due to mutations in theGATA2 gene appears to be a secondary factor that promotes the aggressiveness of non-familialEVI1 positive AML as well as the progression ofprostate cancer.[8][9][10][11]
The GATA2 gene is a member of the evolutionarily conservedGATA transcription factor gene family. Allvertebrate species tested so far, including humans and mice, express 6GATA genes,GATA1 throughGATA6.[12] The humanGATA2 gene is located on the long (or "q") arm ofchromosome 3 at position 21.3 (i.e. the 3q21.3 locus) and consists of 8exons.[13] Two sites, termed C-ZnF and N-ZnF, of the gene code for twoZinc fingerstructural motifs of the GATA2 transcription factor. These sites are critical for regulating the ability of the transcription factor to stimulate its target genes.[14][15]
TheGATA2 gene has at least five separate sites which bind nuclear factors that regulate its expression. One particularly important such site is located inintron 4. This site, termed the 9.5 kb enhancer, is located 9.5kilobases (i.e. kb) down-stream from the gene'stranscript initiation site and is a critically importantenhancer of the gene's expression.[14] Regulation ofGATA2 expression is highly complex. For example, in hematological stem cells, GATA2 transcription factor itself binds to one of these sites and in doing so is part of functionally importantpositive feedbackautoregulation circuit wherein the transcription factor acts to promote its own production; in a second example of a positive feed back circuit, GATA2 stimulates production ofInterleukin 1 beta andCXCL2 which act indirectly to simulateGATA2 expression. In an example of anegative feedback circuit, the GATA2 transcription factor indirectly causes activation of theG protein coupled receptor,GPR65, which then acts, also indirectly, to repressGATA2 gene expression.[14][15] In a second example of negative feed-back, GATA2 transcription factor stimulates the expression of theGATA1 transcription factor which in turn can displace GATA2 transcription factor from its gene-stimulating binding sites thereby limiting GATA2's actions.[16]
TheGata2 gene in mice has a structure similar to its human counterpart, Deletion of both parentalGata2 genes in mice is lethal by day 10 of embryogenesis due to a total failure in theformation of mature blood cells. Inactivation of one mouseGata2 gene is neither lethal nor associated with most of the signs of human GATA2 deficiency; however, these animals do show a ~50% reduction in theirhematopoietic stem cells along with a reduced ability to repopulate the bone marrow of mouse recipients. The latter findings, human clinical studies, and experiments on human tissues support the conclusion that in humans both parentalGATA2 genes are required for sufficient numbers of hematopoietic stem cells to emerge from thehemogenic endothelium duringembryogenesis and for these cells and subsequentprogenitor cells to survive,self-renew, anddifferentiate into mature cells.[14][17][19] As GATA2 deficient individuals age, their deficiency in hematopoietic stem cells worsens, probably as a result of factors such as infections or other stresses. In consequence, the signs and symptoms of their disease appear and/or become progressively more severe.[9] The role of GATA2 deficiency in leading to any of the leukemia types is not understood. Likewise, the role of GATA2 overexpression in non-familial AML as well as development of the blast crisis inchronic myelogenous leukemia and progression of prostate cancer is not understood.[9][15]
Scores of different types of inactivatingGATA mutations have been associated with GATA2 deficiency; these includeframeshift,point,insertion,splice site anddeletion mutations scattered throughout the gene but concentrated in the region encoding the GATA2 transcription factor's C-ZnF, N-ZnF, and 9.5 kb sites. Rare cases of GATA2 deficiency involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types ofGATA mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances.[6][17]
OneGATA2 mutation is again of function type, i.e. it is associated with an increase in the activity rather than levels of GATA2. This mutation substitutes valine for leucine in the 359 amino acid position (i.e. within the N-ZnF site) of the transcription factor and has been detected in individuals undergoing theblast crisis of chronic myelogenous leukemia.[9][20]
Analyses of individuals with AML have discovered many cases of GATA2 deficiency in which one parentalGATA2 gene was not mutated butsilenced byhypermethylation of itsgene promoter. Further studies are required to integrate this hypermethylation-induced form of GATA2 deficiency into the diagnostic category of GATA2 deficiency.[19]
Non-mutational stimulation ofGATA2 expression and consequential aggressiveness in EVI1-positive AML appears due to the ability ofEVI1, a transcription factor, to directly stimulate the expression of theGATA2 gene.[10][11] The reason for the overexpression of GATA2 that begins in the early stages of prostate cancer is unclear but may involve the ability ofFOXA1 to act indirect to stimulate the expression of theGATA2 gene.[11]
The full length GATA2 transcription factor is a moderately sized protein consisting of 480 amino acids. Of its two zinc fingers, C-ZnF (located toward the protein'sC-terminus) is responsible for binding to specificDNA sites while its N-ZnF (located toward the proteinsN-terminus) is responsible for interacting with various othernuclear proteins that regulate its activity. The transcription factor also contains twotransactivation domains and one negative regulatory domain whichinteract with other nuclear proteins to up-regulate and down-regulate, respectively, its activity.[14][21] In promoting embryonic and/or adult-typehaematopoiesis (i.e. maturation of hematological and immunological cells), GATA2 interacts with othertranscription factors (viz.,RUNX1,SCL/TAL1,GFI1,GFI1b,MYB,IKZF1,Transcription factor PU.1,LYL1) and cellular receptors (viz.,MPL,GPR56).[15] In a wide range of tissues, GATA2 similarly interacts withHDAC3,[22]LMO2,[23]POU1F1,[24]POU5F1,[25]PML[26]SPI1,[27] andZBTB16.[28]
GATA2 binds to a specificnucleic acid sequence viz., (T/A(GATA)A/G), on thepromoter andenhancer sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. However, there are thousands of sites in human DNA with this nucleotide sequence but for unknown reasons GATA2 binds to <1% of these. Furthermore, all members of the GATA transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with GATA2 binding or even displace the GATA2 that is already bound to these sites. For example, displacement of GATA2 bond to this sequence by theGATA1 transcription factor appears important for the normal development of some types of hematological stem cells. This displacement phenomenon is termed the "GATA switch". In all events, the actions of GATA2, particularly with referenced to its interactions with many other gene-regulating factors, in controlling its target genes is extremely complex and not fully understood.[6][14][15][16]
The L359V gain of function mutation (see above section on mutation) increases the activity of the GATA2 transcription factor. The mutation occurs during the blast crisis of chronic myelogenous leukemia and is proposed to play a role in the transformation of the chronic and/or accelerated phases of this disease to its blast crisis phase.[9][20]
The repression ofGATA2 expression due tomethylation ofpromoter sites in the GATA2 gene rather than a mutation in this gene has been suggested to be an alternate cause for the GATA2 deficiency syndrome.[19] Thisepigenetic gene silencing also occurs in certain types ofnon-small-cell lung carcinoma and is suggested to have a protective effect on progression of the disease.[21][31]
Elevated levels of GATA2 transcription factor due to overexpression of its gene GATA2 is a common finding in AML. It is associated with a poor prognosis, appears to promote progression of the disease, and therefore proposed to be a target for therapeutic intervention. This overexpression is not due to mutation but rather caused at least in part by the overexpression ofEVI1, a transcription factor that stimulates GATA2 expression.[8]GATA2 overexpression also occurs in prostate cancer where it appears to increasemetastasis in the early stages of androgen-dependent disease and to stimulate prostate cancer cell survival and proliferation through activating by an unknown mechanism the androgen pathway inandrogen-independent (i.e. castration-resistant) disease).[10][11]
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