GATA1

Last updated
GATA1
Protein GATA1 PDB 1gnf.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GATA1 , ERYF1, GATA-1, GF-1, GF1, NF-E1, NFE1, XLANP, XLTDA, XLTT, GATA binding protein 1
External IDs OMIM: 305371 MGI: 95661 HomoloGene: 1549 GeneCards: GATA1
Orthologs
SpeciesHumanMouse
Entrez

2623

14460

Ensembl

ENSG00000102145

ENSMUSG00000031162

UniProt

P15976

P17679

RefSeq (mRNA)

NM_002049

NM_008089

RefSeq (protein)

NP_002040

NP_032115

Location (UCSC) Chr X: 48.79 – 48.79 Mb Chr X: 7.83 – 7.84 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species. [5] [6]

Contents

GATA1 regulates the expression (i.e. formation of the genes' products) of an ensemble of genes that mediate the development of red blood cells and platelets. Its critical roles in red blood cell formation include promoting the maturation of precursor cells, e.g. erythroblasts, to red blood cells and stimulating these cells to erect their cytoskeleton and biosynthesize their oxygen-carrying components viz., hemoglobin and heme. GATA1 plays a similarly critical role in the maturation of blood platelets from megakaryoblasts, promegakaryocytes, and megakaryocytes; the latter cells then shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood. [5] [7]

In consequence of the vital role that GATA1 has in the proper maturation of red blood cells and platelets, inactivating mutations in the GATA1 gene (i.e. mutations that result in the production of no, reduced levels of, or a less active GATA1) cause X chromosome-linked anemic and/or bleeding diseases due to the reduced formation and functionality of red blood cells and/or platelets, respectively, or, under certain circumstances, the pathological proliferation of megakaryoblasts. These diseases include transient myeloproliferative disorder occurring in Down syndrome, acute megakaryoblastic leukemia occurring in Down syndrome, Diamond–Blackfan anemia, and various combined anemia-thrombocytopenia syndromes including a gray platelet syndrome-type disorder. [8] [9] [10]

Reduced levels of GATA1 due to reductions in the translation of GATA1 mRNA into its transcription factor product are associated with promoting the progression of myelofibrosis, i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue and extramedullary hematopoiesis, i.e. the extension of blood cell-forming cells to sites outside of the bone marrow. [11] [12]

Gene

The human GATA1 gene is located on the short (i.e. "p") arm of the X chromosome at position 11.23. It is 7.74 kilobases in length, consists of 6 exons, and codes for a full-length protein, GATA1, of 414 amino acids as well as a shorter one, GATA1-S. GATA1-S lacks the first 83 amino acids of GATA1 and therefore consists of only 331 amino acids. [13] [14] [15] GATA1 codes for two zinc finger structural motifs, C-ZnF and N-ZnF, that are present in both GATA1 and GATA1-S proteins. These motifs are critical for both transcription factors' gene-regulating actions. N-ZnF is a frequent site of disease-causing mutations. Lacking the first 83 amino acids and therefore one of the two activation domains of GATA1, GATA1-S has significantly less gene-regulating activity than GATA1. [8] [15]

Studies in Gata1-knockout mice, i.e. mice lacking the Gata1 gene, indicate that this gene is essential for the development and maintenance of blood-based and/or tissue-based hematological cells, particularly red blood cells and platelets but also eosinophils, basophils, mast cells, and dendritic cells. The knock-out mice die by day 11.5 of their embryonic development due to severe anemia that is associated with absence of cells of the red blood cell lineage, excessive numbers of malformed platelet-precursor cells, and an absence of platelets. These defects reflect the essential role of Gata-1 in stimulating the development, self-renewal, and/or maturation of red blood cell and platelet precursor cells. Studies using mice depleted of their Gata1 gene during adulthood show that: 1) Gata1 is required for the stimulation of erythropoiesis (i.e. increase in red blood cell formation) in response to stress and 2)Gata1-deficient adult mice invariably develop a form of myelofibrosis. [16] [17]

GATA1 proteins

In both GATA1 and GATA1-S, C-ZnF (i.e. C-terminus zinc finger) binds to DNA-specific nucleic acid sequences sites viz., (T/A(GATA)A/G), on the expression-regulating sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. Their N-ZnF (i.e. N-terminus zinc fingers) interacts with an essential transcription factor-regulating nuclear protein, FOG1. FOG1 powerfully promotes or suppresses the actions that the two transcription factors have on most of their target genes. Similar to the knockout of Gata1, knockout of the mouse gene for FOG1, Zfpm1 , causes total failure of red blood cell development and embryonic lethality by day 11.5. Based primarily on mouse studies, it is proposed that the GATA1-FOG1 complex promotes human erythropoiesis by recruiting and binding with at least two gene expression-regulating complexes, Mi-2/NuRD complex (a chromatin remodeler) and CTBP1 (a histone deacetylase) and three gene expression-regulating proteins, SET8 (a GATA1-inhibiting histone methyltransferase), BRG1 (a transcription activator), and Mediator (a transcription co-activator). Other interactions include those with: BRD3 (remodels DNA nucleosomes), [18] [19] [20] BRD4 (binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility), [18] FLI1 (a transcription factor that blocks erythroid differentiation), [21] [22] HDAC1 (a histone deacetylase), [23] LMO2 (regulator of erythrocyte development), [24] ZBTB16 (transcription factor regulating cell cycle progression), [25] TAL1 (a transcription factor), [26] FOG2 (a transcription factor regulator), [27] and GATA2 (Displacement of GATA2 by GATA1, i.e. the "GATA switch", at certain gene-regulating sites is critical for red blood development in mice and, presumably, humans). [17] [28] [29] GATA1-FOG1 and GATA2-FOG1 interactions are critical for platelet formation in mice and may similarly be critical for this in humans. [17]

Physiology and Pathology

GATA1 was first described as a transcription factor that activates the hemoglobin B gene in the red blood cell precursors of chickens. [30] Subsequent studies in mice and isolated human cells found that GATA1 stimulates the expression of genes that promote the maturation of precursor cells (e.g. erythroblasts) to red blood cells while silencing genes that cause these precursors to proliferate and thereby to self-renew. [31] [32] GATA1 stimulates this maturation by, for example, inducing the expression of genes in erythroid cells that contribute to the formation of their cytoskeleton and that make enzymes necessary for the biosynthesis of hemoglobins and heme, the oxygen-carrying components of red blood cells. GATA1-inactivating mutations may thereby result in a failure to produce sufficient numbers of and/or fully functional red blood cells. [5] Also based on mouse and isolated human cell studies, GATA1 appears to play a similarly critical role in the maturation of platelets from their precursor cells. This maturation involves the stimulation of megakaryoblasts to mature ultimately to megakaryocytes which cells shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood. GATA1-inactivating mutations may thereby result in reduced levels of and/or dysfunctional blood platelets. [5] [7]

Reduced levels of GATA1 due to defective translation of GATA1 mRNA in human megakaryocytes is associated with myelofibrosis, i.e. the replacement of bone marrow cells by fibrous tissue. Based primarily on mouse and isolated human cell studies, this myelofibrosis is thought to result from the accumulation of platelet precursor cells in the bone marrow and their release of excessive amounts of cytokines that stimulate bone marrow stromal cells to become fiber-secreting fibroblasts and osteoblasts. Based on mouse studies, low GATA1 levels are also thought to promote the development of splenic enlargement and extramedullary hematopoiesis in human myelofibrosis disease. These effects appear to result directly from the over-proliferation of abnormal platelet precursor cells. [11] [12] [33] [34]

The clinical features associated with inactivating GATA1 mutations or other causes of reduced GATA1 levels vary greatly with respect not only to the types of disease exhibited but also to disease severity. This variation depends on at least four factors. First, inactivating mutations in GATA1 cause X-linked recessive diseases. Males, with only one GATA1 gene, experience the diseases of these mutations while women, with two GATA1 genes, experience no or extremely mild evidence of these diseases unless they have inactivating mutations in both genes or their mutation is dominant negative, i.e. inhibiting the good gene's function. Second, the extent to which a mutation reduces the cellular levels of fully functional GATA1 correlates with disease severity. Third, inactivating GATA1 mutations can cause different disease manifestations. For example, mutations in GATA1's N-ZnF that interfere with its interaction with FOG1 result in reduced red blood cell and platelet levels whereas mutations in N-ZnF that reduce its binding affinity to target genes cause a reduction in red blood cells plus thalassemia-type and porphyria-type symptoms. Fourth, the genetic background of individuals can impact the type and severity of symptoms. For example, GATA1-inactivating mutations in individuals with the extra chromosome 21 of Down syndrome exhibit a proliferation of megakaryoblasts that infiltrate and consequentially directly damage liver, heart, marrow, pancreas, and skin plus secondarily life-threatening damage to the lungs and kidneys. These same individuals can develop secondary mutations in other genes that results in acute megakaryoblastic leukemia. [15] [35]

Genetic disorders

GATA1 gene mutations are associated with the development of various genetic disorders which may be familial (i.e. inherited) or newly acquired. In consequence of its X chromosome location, GATA1 mutations generally have a far greater physiological and clinical impact in men, who have only one X chromosome along with its GATA1 gene, than woman, who have two of these chromosomes and genes: GATA1 mutations lead to X-linked diseases occurring predominantly in males. [15] Mutations in the activation domain of GATA1 (GATA1-S lacks this domain) are associated with the transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome while mutations in the N-ZnF motif of GATA1 and GATA1-S are associated with diseases similar to congenital dyserythropoietic anemia, congenital thrombocytopenia, and certain features that occur in thalassemia, gray platelet syndrome, congenital erythropoietic porphyria, and myelofibrosis. [8]

Transient myeloproliferative disorder

Acquired inactivating mutations in the activation domain of GATA1 are the apparent cause of the transient myeloproliferative disorder that occurs in individuals with Down syndrome. These mutations are frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and therefore a greatly reduced ability to regulate GATA1-targeted genes. The presence of these mutations is restricted to cells bearing the trisomy 21 karyotype (i.e. extra chromosome 21) of Down syndrome: GATA1 inactivating mutations and trisomy 21 are necessary and sufficient for development of the disorder. [35] Transient myeloproliferative disorder consists of a relatively mild but pathological proliferation of platelet-precursor cells, primarily megakaryoblasts, which often show an abnormal morphology that resembles immature myeloblasts (i.e. unipotent stem cells which differentiate into granulocytes and are the malignant proliferating cell in acute myeloid leukemia). Phenotype analyses indicate that these blasts belong to the megakaryoblast series. Abnormal findings include the frequent presence of excessive blast cell numbers, reduced platelet and red blood cell levels, increased circulating white blood cell levels, and infiltration of platelet-precursor cells into the bone marrow, liver, heart, pancreas, and skin. [35] The disorder is thought to develop in utero and is detected at birth in about 10% of individuals with Down syndrome. It resolves totally within ~3 months but in the following 1–3 years progresses to acute megakaryoblastic leukemia in 20% to 30% of these individuals: transient myeloprolierative disorder is a clonal (abnormal cells derived from single parent cells), pre-leukemic condition and is classified as a myelodysplastic syndrome disease. [7] [8] [16] [35]

Acute megakaryoblastic leukemia

Acute megakaryoblastic leukemia is a subtype of acute myeloid leukemia that is extremely rare in adults and, although still rare, more common in children. The childhood disease is classified into two major subgroups based on its occurrence in individuals with or without Down syndrome. The disease in Down syndrome occurs in 20% to 30% of individuals who previously had transient myeloproliferative disorder. Their GATA1 mutations are frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and thus a greatly reduced ability to regulate GATA1-targeted genes. Transient myeloproliferative disorder is detected at or soon after birth and generally resolves during the next months but is followed within 1–3 years by acute megakaryoblastic leukemia. [7] During this 1-3 year interval, individuals accumulate multiple somatic mutations in cells bearing inactivating GATA1 mutations plus trisomy 21. These mutations are thought to result from the uncontrolled proliferation of blast cells caused by the GATAT1 mutation in the presence of the extra chromosome 21 and to be responsible for progression of the transient disorder to leukemia. The mutations occur in one or, more commonly, multiple genes including: TP53, RUNX1, FLT3, ERG, DYRK1A, CHAF1B, HLCS, CTCF, STAG2, RAD21, SMC3, SMC1A, NIPBL, SUZ12, PRC2, JAK1, JAK2, JAK3, MPL, KRAS, NRAS, SH2B3 , and MIR125B2 which is the gene for microRNA MiR125B2. [7] [36]

Diamond–Blackfan anemia

Diamond–Blackfan anemia is a familial (i.e. inherited) (45% of cases) or acquired (55% of cases) genetic disease that presents in infancy or, less commonly, later childhood as aplastic anemia and the circulation of abnormally enlarged red blood cells. Other types of blood cell and platelets circulate at normal levels and appear normal in structure. About half of affected individuals have various birth defects. [10] The disease is regarded as a uniformly genetic disease although the genes causing it have not been identified in ~30% of cases. In virtually all the remaining cases, autosomal recessive inactivating mutations occur in any one of 20 of the 80 genes encoding ribosomal proteins. About 90% of the latter mutations occur in 6 ribosomal protein genes viz., RPS19, RPL5, RPS26, RPL11, RPL35A , and RPS24 . [8] [10] However, several cases of familial Diamond–Blackfan anemia have been associated with GATA1 gene mutations in the apparent absence of a mutation in ribosomal protein genes. These GATA1 mutations occur in an exon 2 splice site or the start codon of GATA1, cause the production of the GATA1-S in the absence of the GATA1 transcription factor, and therefore are gene-inactivating in nature. It is proposed that these GATA1 mutations are a cause for Diamond Blackfan anemia. [8] [15] [16]

Combined anemia-thrombocytopenia syndromes

Certain GATA1-inactivatng mutations are associated with familial or, less commonly, sporadic X-linked disorders that consist of anemia and thrombocytopenia due to a failure in the maturation of red blood cell and platelet precursors plus other hematological abnormalities. These GATA1 mutations are identified by an initial letter identifying the normal amino acid followed by a number giving the position of this amino acid in GATA1, followed by a final letter identifying the amino acid substituted for the normal one. The amino acids are identified as V=valine; M=methionine; G=glycine; S=serine, D=aspartic acid; Y=tyrosine, R=arginine; W=tryptophan, Q=glutamine). These mutations and some key abnormalities they cause are: [8] [16] [37] [38]

The Gray platelet syndrome is a rare congenital bleeding disorder caused by reductions or absence of alpha-granules in platelets. Alpha-granules contain various factors which contribute to blood clotting and other functions. In their absence, platelets are defective. The syndrome is commonly considered to result solely from mutations in the NBEAL2 gene located on human chromosome 3 at position p21. In these cases, the syndrome follows autosomal recessive inheritance, causes a mild to moderate bleeding tendency, and may be accompanied by a defect in the secretion of the granule contents in neutrophils. There are other causes for a congenital platelet alpha-granule-deficient bleeding disorder viz., the autosomal recessive disease of Arc syndrome caused by mutations in either the VPS33B (on human chromosome 15 at q26) or VIPAS39 (on chromosome 14 at q34); the autosomal dominant disease of GFI1B-related syndrome caused by mutations in GFI1B (located on human chromosome 9 at q34); and the disease caused by R216W and R216Q mutations in GATA1. The GATA1 mutation-related disease resembles the one caused by NBEAL2 mutations in that it is associated with the circulation of a reduced number (i.e. thrombocytopenia) of abnormally enlarged (i.e. macrothrombocytes), alpha-granule deficient platelets. It differs from the NBEAL2-induced disease in that it is X chromosome-linked, accompanied by a moderately severe bleeding tendency, and associated with abnormalities in red blood cells (e.g. anemia, a thalassemia-like disorder due to unbalanced hemoglobin production, and/or a porphyria-like disorder. [40] [37] A recent study found that GATA1 is a strong enhancer of NBEAL2 expression and that the R216W and R216Q inactivating mutations in GATA1 may cause the development of alpha granule-deficient platelets by failing to stimulate the expression of NBDAL2 protein. [41] Given these differences, the GATA1 mutation-related disorder appears better classified as clinically and pathologically different than the gray platelet syndrome. [40]

GATA1 in myelofibrosis

Myelofibrosis is a rare hematological malignancy characterized by progressive fibrosis of the bone marrow, extramedullary hematopoiesis (i.e. formation of blood cells outside of their normal site in the bone marrow), variable reductions in the levels of circulating blood cells, increases in the circulating levels of the precursors to the latter cells, abnormalities in platelet precursor cell maturation, and the clustering of grossly malformed megakaryocytes in the bone marrow. Ultimately, the disease may progress to leukemia. Recent studies indicate that the megakaryocytes but not other cell types in rare cases of myelofibrosis have greatly reduced levels of GATA1 as a result of a ribosomal deficiency in translating GATA1 mRNA into GATA1 transcription factor. The studies suggest that these reduced levels of GATA1 contribute to the progression of myelofibrosis by leading to an impairment in platelet precursor cell maturation, by promoting extramedullary hematopoiesis, and, possibly, by contributing to its leukemic transformation. [12] [33] [34]

Related Research Articles

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature 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 include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Eosinophilia</span> Blood condition

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, AR, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

<span class="mw-page-title-main">Myeloproliferative neoplasm</span> Overproduction of blood cells in the bone marrow

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

Severe congenital neutropenia (SCN), also often known as Kostmann syndrome or disease, is a group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia, usually without other physical malformations. SCN manifests in infancy with life-threatening bacterial infections. It causes severe pyogenic infections. It can be caused by autosomal dominant inheritance of the ELANE gene, autosomal recessive inheritance of the HAX1 gene. There is an increased risk of leukemia and myelodysplastic cancers.

Diamond–Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA causes low red blood cell counts (anemia), without substantially affecting the other blood components, which are usually normal. This is in contrast to Shwachman–Bodian–Diamond syndrome, in which the bone marrow defect results primarily in neutropenia, and Fanconi anemia, where all cell lines are affected resulting in pancytopenia. There is a risk to develop acute myelogenous leukemia (AML) and certain other cancers.

<span class="mw-page-title-main">Gray platelet syndrome</span> Medical condition

Gray platelet syndrome (GPS), or platelet alpha-granule deficiency, is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in these granules into the marrow, causing myelofibrosis. The name derives from the initial observation of gray appearance of platelets with a paucity of granules on blood films from a patient with a lifelong bleeding disorder.

<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

<span class="mw-page-title-main">KLF1</span> Protein-coding gene in the species Homo sapiens

Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturation of erythroid cells.

<span class="mw-page-title-main">PDGFRB</span> Protein-coding gene in the species Homo sapiens

Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the PDGFRB gene. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies.

<span class="mw-page-title-main">GATA2</span> Protein-coding gene in the species Homo sapiens

GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic 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.

<span class="mw-page-title-main">GATA3</span> Protein-coding gene in the species Homo sapiens

GATA3 is a transcription factor that in humans is encoded by the GATA3 gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.

<span class="mw-page-title-main">Thrombopoietin receptor</span> Protein-coding gene in the species Homo sapiens

The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 is a protein that in humans is encoded by the MPL oncogene.

<span class="mw-page-title-main">Zinc finger protein ZFPM1</span> Protein found in humans

Zinc finger protein ZFPM1 also known as friend of GATA protein 1(FOG-1) is a protein that in humans is encoded by the ZFPM1 gene. It is a cofactor of the GATA1 transcription factor.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Medical condition

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

<span class="mw-page-title-main">Emberger syndrome</span> Medical condition

The Emberger syndrome is a rare, autosomal dominant, genetic disorder caused by familial or sporadic inactivating mutations in one of the two parental GATA2 genes. The mutation results in a haploinsufficiency in the levels of the gene's product, the GATA2 transcription factor. This transcription factor is critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissues. The syndrome includes as its primary symptoms: serious abnormalities of the blood such as the myelodysplastic syndrome and acute myeloid leukemia; lymphedema of the lower limbs, and sensorineural hearing loss. However, the anomalies caused by GATA2 mutations are highly variable with some individuals showing little or no such symptoms even in old age while others exhibit non-malignant types of hematological anomalies; lymphedema in areas besides the lower limbs, little or no hearing loss; or anomalies in other tissues. The syndrome may present with relatively benign signs and/or symptoms and then progress rapidly or slowly to the myelodysplastic syndrome and/or acute myeloid leukemia. Alternatively, it may present with one of the latter two life-threatening disorders.

GATA2 deficiency is a grouping of several disorders caused by common defect, namely, familial or sporadic inactivating mutations in one of the two parental GATA2 genes. Being the gene haploinsufficient, mutations that cause a reduction in the cellular levels of the gene's product, GATA2, are autosomal dominant. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to severe organ failure, opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemia. GATA2 deficiency is a life-threatening and precancerous condition.

Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses as well as infants in their first few months of life.

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  13. ↑ "GATA1 GATA binding protein 1 [Homo sapiens (human)] - Gene - NCBI".
  14. ↑ "Genatlas sheet".
  15. 1 2 3 4 5 Shimizu R, Yamamoto M (August 2016). "GATA-related hematologic disorders". Experimental Hematology. 44 (8): 696–705. doi: 10.1016/j.exphem.2016.05.010 . PMID   27235756.
  16. 1 2 3 4 Crispino JD, Horwitz MS (April 2017). "GATA factor mutations in hematologic disease". Blood. 129 (15): 2103–2110. doi:10.1182/blood-2016-09-687889. PMC   5391620 . PMID   28179280.
  17. 1 2 3 Katsumura KR, Bresnick EH (April 2017). "The GATA factor revolution in hematology". Blood. 129 (15): 2092–2102. doi:10.1182/blood-2016-09-687871. PMC   5391619 . PMID   28179282.
  18. 1 2 Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, Cheng Y, Billin AN, Hardison RC, Mackay JP, Blobel GA (May 2011). "Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes". Proceedings of the National Academy of Sciences of the United States of America. 108 (22): E159-68. doi: 10.1073/pnas.1102140108 . PMC   3107332 . PMID   21536911.
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  20. ↑ Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA (Feb 2015). "Functions of BET proteins in erythroid gene expression". Blood. 125 (18): 2825–34. doi:10.1182/blood-2014-10-607309. PMC   4424630 . PMID   25696920.,
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  23. ↑ Watamoto K, Towatari M, Ozawa Y, Miyata Y, Okamoto M, Abe A, Naoe T, Saito H (Dec 2003). "Altered interaction of HDAC5 with GATA-1 during MEL cell differentiation". Oncogene. 22 (57): 9176–84. doi:10.1038/sj.onc.1206902. PMID   14668799. S2CID   24491249.
  24. ↑ Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH (Oct 1995). "Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1". Proceedings of the National Academy of Sciences of the United States of America. 92 (21): 9585–9. Bibcode:1995PNAS...92.9585O. doi: 10.1073/pnas.92.21.9585 . PMC   40846 . PMID   7568177.
  25. ↑ Labbaye C, Quaranta MT, Pagliuca A, Militi S, Licht JD, Testa U, Peschle C (Sep 2002). "PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein". Oncogene. 21 (43): 6669–79. doi: 10.1038/sj.onc.1205884 . PMID   12242665.
  26. ↑ Goardon N, Lambert JA, Rodriguez P, Nissaire P, Herblot S, Thibault P, Dumenil D, Strouboulis J, Romeo PH, Hoang T (Jan 2006). "ETO2 coordinates cellular proliferation and differentiation during erythropoiesis". The EMBO Journal. 25 (2): 357–66. doi:10.1038/sj.emboj.7600934. PMC   1383517 . PMID   16407974.
  27. ↑ Holmes M, Turner J, Fox A, Chisholm O, Crossley M, Chong B (Aug 1999). "hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation". The Journal of Biological Chemistry. 274 (33): 23491–8. doi: 10.1074/jbc.274.33.23491 . PMID   10438528.
  28. ↑ Fujiwara Y, Browne CP, Cunniff K, Goff SC, Orkin SH (Oct 1996). "Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1". Proceedings of the National Academy of Sciences of the United States of America. 93 (22): 12355–8. Bibcode:1996PNAS...9312355F. doi: 10.1073/pnas.93.22.12355 . PMC   37995 . PMID   8901585.
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  30. ↑ Evans T, Reitman M, Felsenfeld G (Aug 1988). "An erythrocyte-specific DNA-binding factor recognizes a regulatory sequence common to all chicken globin genes". Proceedings of the National Academy of Sciences of the United States of America. 85 (16): 5976–80. Bibcode:1988PNAS...85.5976E. doi: 10.1073/pnas.85.16.5976 . PMC   281888 . PMID   3413070.
  31. ↑ Welch JJ, Watts JA, Vakoc CR, Yao Y, Wang H, Hardison RC, Blobel GA, Chodosh LA, Weiss MJ (Nov 2004). "Global regulation of erythroid gene expression by transcription factor GATA-1". Blood. 104 (10): 3136–47. doi: 10.1182/blood-2004-04-1603 . PMID   15297311.
  32. ↑ Cheng Y, Wu W, Kumar SA, Yu D, Deng W, Tripic T, King DC, Chen KB, Zhang Y, Drautz D, Giardine B, Schuster SC, Miller W, Chiaromonte F, Zhang Y, Blobel GA, Weiss MJ, Hardison RC (Dec 2009). "Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression". Genome Research. 19 (12): 2172–84. doi:10.1101/gr.098921.109. PMC   2792182 . PMID   19887574.
  33. 1 2 Yang N, Park S, Cho MS, Lee M, Hong KS, Mun YC, Seong CM, Huh HJ, Huh J (July 2018). "GATA1 Expression in BCR/ABL1-negative Myeloproliferative Neoplasms". Annals of Laboratory Medicine. 38 (4): 296–305. doi:10.3343/alm.2018.38.4.296. PMC   5895858 . PMID   29611379.
  34. 1 2 Gilles L, Arslan AD, Marinaccio C, Wen QJ, Arya P, McNulty M, Yang Q, Zhao JC, Konstantinoff K, Lasho T, Pardanani A, Stein B, Plo I, Sundaravel S, Wickrema A, Migliaccio A, Gurbuxani S, Vainchenker W, Platanias LC, Tefferi A, Crispino JD (April 2017). "Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis". The Journal of Clinical Investigation. 127 (4): 1316–1320. doi:10.1172/JCI82905. PMC   5373858 . PMID   28240607.
  35. 1 2 3 4 Gamis AS, Smith FO (November 2012). "Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder". British Journal of Haematology. 159 (3): 277–87. doi: 10.1111/bjh.12041 . PMID   22966823. S2CID   37593917.
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  37. 1 2 Balduini CL, Savoia A (December 2012). "Genetics of familial forms of thrombocytopenia". Human Genetics. 131 (12): 1821–32. doi:10.1007/s00439-012-1215-x. PMID   22886561. S2CID   14396101.
  38. ↑ Russo R, Andolfo I, Gambale A, De Rosa G, Manna F, Arillo A, Wandroo F, Bisconte MG, Iolascon A (September 2017). "GATA1 erythroid-specific regulation of SEC23B expression and its implication in the pathogenesis of congenital dyserythropoietic anemia type II". Haematologica. 102 (9): e371–e374. doi:10.3324/haematol.2016.162966. PMC   5685218 . PMID   28550189.
  39. ↑ "Rs113966884 RefSNP Report - DBSNP - NCBI".
  40. 1 2 Nurden AT, Nurden P (July 2016). "Should any genetic defect affecting α-granules in platelets be classified as gray platelet syndrome?". American Journal of Hematology. 91 (7): 714–8. doi: 10.1002/ajh.24359 . PMID   26971401. S2CID   27009005.
  41. ↑ Wijgaerts A, Wittevrongel C, Thys C, Devos T, Peerlinck K, Tijssen MR, Van Geet C, Freson K (April 2017). "The transcription factor GATA1 regulates NBEAL2 expression through a long-distance enhancer". Haematologica. 102 (4): 695–706. doi:10.3324/haematol.2016.152777. PMC   5395110 . PMID   28082341.

Further reading

Other types of GATA2 mutations cause the over-expression of the GATA2 transcription factor. This overexpression is associated with the development of non-familial AML. Apparently, the GATA2 gene's expression level must be delicately balanced between deficiency and excess in order to avoid life-threatening disease. [1] [2]

  1. ↑ Mir MA, Kochuparambil ST, Abraham RS, Rodriguez V, Howard M, Hsu AP, Jackson AE, Holland SM, Patnaik MM (April 2015). "Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations". Cancer Medicine. 4 (4): 490–9. doi:10.1002/cam4.384. PMC   4402062 . PMID   25619630.
  2. ↑ Katsumura KR, Bresnick EH (April 2017). "The GATA factor revolution in hematology". Blood. 129 (15): 2092–2102. doi:10.1182/blood-2016-09-687871. PMC   5391619 . PMID   28179282.
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