GATA2
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GATA2 or GATA-binding factor 2 is a
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
, i.e. a
nuclear protein A nuclear protein is a protein found in the cell nucleus. Proteins are transported inside the nucleus with the help of Nuclear Pore Complex, the nuclear pore complex, which acts a barrier between cytoplasm and nuclear membrane. The import and expor ...
which regulates the expression of
genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. It regulates many genes that are critical for the
embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...
, self-renewal, maintenance, and functionality of blood-forming, lymphatic system-forming, and other tissue-forming
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
s. GATA2 is encoded by the ''GATA2'' gene, a gene which often suffers
germline In biology and genetics, the germline is the population of a multicellular organism's cells that develop into germ cells. In other words, they are the cells that form gametes ( eggs and sperm), which can come together to form a zygote. They dif ...
and
somatic Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous syst ...
mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases. Inactivating mutations of the ''GATA2'' gene cause a reduction in the cellular levels of GATA2 and the development of a wide range of familial hematological, immunological, lymphatic, and/or other disorders that are grouped together into a common disease termed GATA2 deficiency. Less commonly, these disorders are associated with non-familial (i.e. sporadic or acquired) ''GATA'' inactivating mutations. GATA2 deficiency often begins with seemingly benign abnormalities but if untreated progresses to life-threatening
opportunistic infection An opportunistic infection is an infection that occurs most commonly in individuals with an immunodeficiency disorder and acts more severe on those with a weakened immune system. These types of infections are considered serious and can be caused b ...
s, virus-induced cancers, lung failure, the
myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
(i.e. MDS), and/or
acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
, principally
acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
(AML), less commonly chronic myelomonocytic leukemia (CMML), and rarely a lymphoid leukemia. Overexpression of the GATA2 transcription factor that is not due to mutations in the ''GATA2'' gene appears to be a secondary factor that promotes the aggressiveness of non-familial EVI1 positive AML as well as the progression of
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
.


''GATA2'' gene

The GATA2 gene is a member of the evolutionarily conserved
GATA transcription factor The GATA transcription factor family consists of six DNA-binding proteins (GATA1-6) that regulates transcription of DNA due to their ability to bind to the DNA sequence "GATA" which can therefore affect different diseases. These six proteins a ...
gene family. All
vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...
species tested so far, including humans and mice, express 6 ''GATA'' genes, ''GATA1'' through ''GATA6''. The human ''GATA2'' gene is located on the long (or "q") arm of
chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans more than 201 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA ...
at position 21.3 (i.e. the 3q21.3 locus) and consists of 8
exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...
. Two sites, termed C-ZnF and N-ZnF, of the gene code for two
Zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...
structural motif In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...
s of the GATA2 transcription factor. These sites are critical for regulating the ability of the transcription factor to stimulate its target genes. The ''GATA2'' gene has at least five separate sites which bind nuclear factors that regulate its expression. One particularly important such site is located in
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...
4. This site, termed the 9.5 kb enhancer, is located 9.5 kilobases (i.e. kb) down-stream from the gene's transcript initiation site and is a critically important enhancer of the gene's expression. Regulation of ''GATA2'' 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 important
positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop where the outcome of a process reinforces the inciting process to build momentum. As such, these forces can exacerbate the effects ...
autoregulation circuit wherein the transcription factor acts to promote its own production; in a second example of a positive feed back circuit, GATA2 stimulates production of
Interleukin 1 beta Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
and CXCL2 which act indirectly to simulate ''GATA2'' expression. In an example of a
negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...
circuit, the GATA2 transcription factor indirectly causes activation of the
G protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...
, GPR65, which then acts, also indirectly, to repress ''GATA2'' gene expression. In a second example of negative feed-back, GATA2 transcription factor stimulates the expression of the
GATA1 GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded b ...
transcription factor which in turn can displace GATA2 transcription factor from its gene-stimulating binding sites thereby limiting GATA2's actions. The human ''GATA2'' gene is expressed in hematological bone marrow cells at the
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
and later
progenitor cell A progenitor cell is a biological cell that can differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor cells. Progenitor cells can only diffe ...
stages of their
development Development or developing may refer to: Arts *Development (music), the process by which thematic material is reshaped * Photographic development *Filmmaking, development phase, including finance and budgeting * Development hell, when a proje ...
. Increases and/or decreases in the gene's expression regulate the self-renewal, survival, and progression of these immature cells toward their final mature forms viz.,
erythrocytes Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
, certain types of
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s (i.e.
B cells B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
, NK cells, and
T helper cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
),
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
,
neutrophils Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...
,
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s, plasmacytoid dendritic cells,
macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
and mast cells. The gene is likewise critical for the formation of the
lymphatic system The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lympha ...
, particularly for the development of its valves. The human gene is also expressed in
endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...
, some non-hematological stem cells, the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
, and, to lesser extents, prostate, endometrium, and certain cancerous tissues. The ''Gata2'' gene in mice has a structure similar to its human counterpart, Deletion of both parental ''Gata2'' genes in mice is lethal by day 10 of embryogenesis due to a total failure in the formation of mature blood cells. Inactivation of one mouse ''Gata2'' gene is neither lethal nor associated with most of the signs of human GATA2 deficiency; however, these animals do show a ~50% reduction in their
hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...
s 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 parental ''GATA2'' genes are required for sufficient numbers of hematopoietic stem cells to emerge from the hemogenic endothelium during
embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...
and for these cells and subsequent
progenitor cells A progenitor cell is a Cell (biology), biological cell that can Cellular differentiation, differentiate into a specific cell type. Stem cell, Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than ...
to survive, self-renew, and differentiate into mature cells. 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. 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 in
chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumula ...
and progression of prostate cancer is not understood.


Mutations

Scores of different types of inactivating ''GATA'' mutations have been associated with GATA2 deficiency; these include frameshift, point, insertion, splice site and deletion 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 of ''GATA'' mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances. One ''GATA2'' mutation is a gain 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 the blast crisis of chronic myelogenous leukemia.


Pathological inhibition

Analyses of individuals with AML have discovered many cases of GATA2 deficiency in which one parental ''GATA2'' gene was not mutated but silenced by
hypermethylation Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms ...
of its
gene promoter In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription (genetics), transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can hav ...
. Further studies are required to integrate this hypermethylation-induced form of GATA2 deficiency into the diagnostic category of GATA2 deficiency.


Pathological stimulation

Non-mutational stimulation of ''GATA2'' expression and consequential aggressiveness in EVI1-positive AML appears due to the ability of EVI1, a transcription factor, to directly stimulate the expression of the ''GATA2'' gene. The reason for the overexpression of GATA2 that begins in the early stages of prostate cancer is unclear but may involve the ability of FOXA1 to act indirect to stimulate the expression of the ''GATA2'' gene.


GATA2

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's
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...
) is responsible for binding to specific
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
sites while its N-ZnF (located toward the proteins
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
) is responsible for interacting with various other nuclear proteins that regulate its activity. The transcription factor also contains two
transactivation domain The transactivation domain or trans-activating domain (TAD) is a transcription factor scaffold domain which contains binding sites for other proteins such as transcription coregulators. These binding sites are frequently referred to as activatio ...
s and one negative regulatory domain which interact with other nuclear proteins to up-regulate and down-regulate, respectively, its activity. In promoting embryonic and/or adult-type
haematopoiesis Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
(i.e. maturation of hematological and immunological cells), GATA2 interacts with other
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
(viz.,
RUNX1 Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) and it is a protein that is encoded by the ''RUNX1'' gene, in humans. RUNX1 is a transcription facto ...
, SCL/TAL1, GFI1, GFI1b, MYB, IKZF1, Transcription factor PU.1,
LYL1 Protein lyl-1 is a protein that in humans is encoded by the ''LYL1'' gene. Interactions LYL1 has been shown to interact with TCF3 Transcription factor 3 (E2A immunoglobulin enhancer-binding factors E12/E47), also known as TCF3, is a protei ...
) and cellular receptors (viz., MPL, GPR56). In a wide range of tissues, GATA2 similarly interacts with
HDAC3 Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice. Function Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...
,
LMO2 LIM domain only 2 (rhombotin-like 1), also known as LMO2, RBTNL1, RBTN2, RHOM2, LIM Domain Only Protein 2, TTG2, and T-Cell Translocation Protein 2, is a protein which in humans is encoded by the ''LMO2'' gene. Structure LMO2 is characterized ...
, POU1F1, POU5F1, PML SPI1, and ZBTB16. GATA2 binds to a specific
nucleic acid sequence A nucleic acid sequence is a succession of Nucleobase, bases within the nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. This succession is denoted by a series of a set of five different letters that indicate the orde ...
viz., (T/A(GATA)A/G), on the promoter and enhancer 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 the
GATA1 GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded b ...
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.


''GATA2''-related disorders


Inactivating ''GATA2'' mutations

Familial and sporadic inactivating mutations in one of the two parental ''GATA2''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s causes a reduction, i.e. a
haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...
, in the cellular levels of the GATA2 transcription factor. In consequence, individuals commonly develop a disease termed GATA2 deficiency. GATA2 deficiency is a grouping of various clinical presentations in which GATA2 haploinsufficiency results in the development over time of hematological, immunological, lymphatic, and/or other presentations that may begin as apparently benign abnormalities but commonly progress to life-threatening
opportunistic infection An opportunistic infection is an infection that occurs most commonly in individuals with an immunodeficiency disorder and acts more severe on those with a weakened immune system. These types of infections are considered serious and can be caused b ...
s, virus infection-induced cancers, the
myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
, and/or
leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
s, particularly AML. The various presentations of GATA2 deficiency include all cases of Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC) and the Emberger syndrome as well as a significant percentage of cases of familial myelodysplastic syndrome/acute myeloid leukemia, congenital neutropenia, chronic myelomonocytic leukemia,
aplastic anemia Aplastic anemia (AA) is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. Normally, blood cells are produced in the bone marrow by stem cells that reside there, but patients with aplastic anemia ...
, and several other presentations.


Activating ''GATA2'' mutation

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.


Repression of ''GATA2''

The repression of ''GATA2'' expression due to
methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...
of promoter 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. This epigenetic gene silencing also occurs in certain types of
non-small-cell lung carcinoma Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...
and is suggested to have a protective effect on progression of the disease.


Overexpression of ''GATA2''

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 of EVI1, a transcription factor that stimulates GATA2 expression. ''GATA2'' overexpression also occurs in prostate cancer where it appears to increase
metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
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 in androgen-independent (i.e. castration-resistant) disease).


See also

*
GATA transcription factor The GATA transcription factor family consists of six DNA-binding proteins (GATA1-6) that regulates transcription of DNA due to their ability to bind to the DNA sequence "GATA" which can therefore affect different diseases. These six proteins a ...
* GATA2 deficiency * MonoMAC * Emberger syndrome


References


Further reading

* * * * * * * * * * * * * * * * * * * *


External links

* * * {{DEFAULTSORT:Gata2 Transcription factors