Key Points
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GATA1 is an important transcription factor for the differentiation of the erythroid and megakaryocytic cell lineages through cooperative regulation of key molecules associated with proliferation, differentiation and apoptosis.
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Mice that harbour a heterozygous Gata1-knockdown allele (Gata1.05) frequently develop erythroblastic leukaemias, showing that compromised Gata1 expression can be a causal factor in erythroid leukaemia.
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Mutations in GATA1 that lead to the production of an amino-terminally truncated short form of the GATA1 protein contribute to cases of acute megakaryoblastic leukaemia and transient myeloproliferative disorder (TMD) that are seen in Down syndrome patients.
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Mice expressing the short form of GATA1 protein exhibit an unusual accumulation of immature megakaryocytic progenitors during the embryonic and neonatal stages, and these hyperproliferative megakaryoblasts rapidly disappear during weaning, showing good agreement with the clinical course in TMD cases.
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Leukaemias that are related to the quantitative and qualitative deficit of GATA1 function are collectively referred to as the GATA1-related leukaemias.
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GATA1-related leukaemogenesis is a paradigm for multi-step disease and this process is likely to involve the participation of currently unidentified modifier genes.
Abstract
GATA1 is a prototypical lineage-restricted transcription factor that is central to the correct differentiation, proliferation and apoptosis of erythroid and megakaryocytic cells. Mutations in GATA1 can generate a truncated protein, which contributes to the genesis of transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukaemia (AMKL) in infants with Down syndrome. Similarly, Gata1 knockdown to 5% of its wild-type level causes high incidence of erythroid leukaemia in mice. The GATA1-related leukaemias in both human and mouse could provide important insights into the mechanism of multi-step leukaemogenesis. Efforts are afoot to produce mouse models that are reflective of TMD and AMKL.
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References
Iwasaki, H. & Akashi, K. Myeloid lineage commitment from the hematopoietic stem cell. Immunity 26, 726–740 (2007).
Scandura, J. M., Boccuni, P., Cammenga, J. & Nimer, S. D. Transcription factor fusions in acute leukemia: variations on a theme. Oncogene 21, 3422–3444 (2002).
Ohneda, K. et al. A minigene containing four discrete cis elements recapitulates GATA-1 gene expression in vivo. Genes Cells 7, 1243–1254 (2002).
Lowry, J. A. & Atchley, W. R. Molecular evolution of the GATA family of transcription factors: conservation within the DNA-binding domain. J. Mol. Evol. 50, 103–115 (2000).
Cantor, A. B. & Orkin, S. H. Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21, 3368–3376 (2002).
Patient, R. K. & McGhee, J. D. The GATA family (vertebrates and invertebrates). Curr. Opin. Genet. Dev. 12, 416–422 (2002).
Molkentin, J. D. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J. Biol. Chem. 275, 38949–38952 (2000).
Morrisey, E. E., Ip, H. S., Tang, Z., Lu, M. M. & Parmacek, M. S. GATA-5: a transcriptional activator expressed in a novel temporally and spatially-restricted pattern during embryonic development. Dev. Biol. 183, 21–36 (1997).
Grogan, J. L. & Locksley, R. M. T helper cell differentiation: on again, off again. Curr. Opin. Immunol. 14, 366–372 (2002).
Shimizu, R. & Yamamoto, M. Gene expression regulation and domain function of hematopoietic GATA factors. Semin. Cell Dev. Biol. 16, 129–136 (2005).
Duncan, S. A. Generation of embryos directly from embryonic stem cells by tetraploid embryo complementation reveals a role for GATA factors in organogenesis. Biochem. Soc. Trans. 33, 1534–1536 (2005).
Bresnick, E. H., Martowicz, M. L., Pal, S. & Johnson, K. D. Developmental control via GATA factor interplay at chromatin domains. J. Cell Physiol. 205, 1–9 (2005).
Takahashi, S. et al. GATA factor transgenes under GATA-1 locus control rescue germ line GATA-1 mutant deficiencies. Blood 96, 910–916 (2000).
Shimizu, R., Takahashi, S., Ohneda, K., Engel, J. D. & Yamamoto, M. In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis. EMBO J. 20, 5250–5260 (2001). This report describes a transgenic complementation rescue assay to clarify in vivo function of the GATA1NT domain.
Hosoya-Ohmura, S. et al. GATA-4 incompletely substitutes for GATA-1 in promoting both primitive and definitive erythropoiesis in vivo. J. Biol. Chem. 281, 32820–32830 (2006).
Rylski, M. et al. GATA-1-mediated proliferation arrest during erythroid maturation. Mol. Cell. Biol. 23, 5031–5042 (2003).
Nichols, K. E. et al. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nature Genet. 24, 266–270 (2000). The first report of inherited mutation of GATA1 related to human diseases.
Mehaffey, M. G., Newton, A. L., Gandhi, M. J., Crossley, M. & Drachman, J. G. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood 98, 2681–2688 (2001).
Freson, K. et al. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98, 85–92 (2001).
Freson, K. et al. Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum. Mol. Genet. 11, 147–152 (2002).
Yu, C. et al. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood 100, 2040–2045 (2002).
Phillips, J. D., Steensma, D. P., Pulsipher, M. A., Spangrude, G. J. & Kushner, J. P. Congenital erythropoietic porphyria due to a mutation in GATA-1: the first trans-acting mutation causative for a human porphyria. Blood 109, 2618–2621 (2006).
Ito, E. et al. Erythroid transcription factor GATA-1 is abundantly transcribed in mouse testis. Nature 362, 466–468 (1993).
Yomogida, K. et al. Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells. Development 120, 1759–1766 (1994).
Takahashi, S. et al. Arrest in primitive erythroid cell development caused by promoter- specific disruption of the GATA-1 gene. J. Biol. Chem. 272, 12611–12615 (1997). This paper describes the generation of the first Gata1 -knockdown ( Gata1.05 ) mouse line.
Fujiwara, Y., Browne, C. P., Cunniff, K., Goff, S. C. & Orkin, S. H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Natl Acad. Sci. USA 93, 12355–12358 (1996).
Lyon, M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373 (1961).
Shimizu, R. et al. Leukemogenesis caused by incapacitated GATA-1 function. Mol. Cell. Biol. 24, 10814–10825 (2004). This paper demonstrates that quantitative reduction of the Gata1 expression gives rise to perturbation in erythropoiesis, leading to leukemogenesis.
Onodera, K. et al. GATA-1 transcription is controlled by distinct regulatory mechanisms during primitive and definitive erythropoiesis. Proc. Natl Acad. Sci. USA 94, 4487–4492 (1997).
Nishimura, S. et al. A GATA box in the GATA-1 gene hematopoietic enhancer is a critical element in the network of GATA factors and sites that regulate this gene. Mol. Cell. Biol. 20, 713–723 (2000).
Kobayashi, M. & Yamamoto, M. Regulation of GATA1 gene expression. J. Biochem. 142, 1–10 (2007).
Suzuki, N. et al. Identification and characterization of 2 types of erythroid progenitors that express GATA-1 at distinct levels. Blood 102, 3575–3583 (2003).
Wang, Q. et al. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc. Natl Acad. Sci. USA 93, 3444–3449 (1996).
Song, W. J. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genet. 23, 166–175 (1999).
Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G. & Downing, J. R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330 (1996).
Motoda, L. et al. Runx1 protects hematopoietic stem/progenitor cells from oncogenic insult. Stem Cells 25, 2976–2986 (2007).
Lloberas, J., Soler, C. & Celada, A. The key role of PU.1/SPI-1 in B cells, myeloid cells and macrophages. Immunol. Today 20, 184–189 (1999).
Scott, E. W., Simon, M. C., Anastasi, J. & Singh, H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265, 1573–1577 (1994).
Dakic, A. et al. PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. J. Exp. Med. 201, 1487–1502 (2005).
Steidl, U. et al. A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J. Clin. Invest. 117, 2611–2620 (2007).
Rosenbauer, F. et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nature Genet. 36, 624–630 (2004). This paper and references 28 and 34 describe the leukaemogenesis that is related to the attenuated expression of key transcription factors in human and mouse.
Metcalf, D. et al. Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia. Proc. Natl Acad. Sci. USA 103, 1486–1491 (2006).
Nakano, T., Kodama, H. & Honjo, T. In vitro development of primitive and definitive erythrocytes from different precursors. Science 272, 722–724 (1996).
Pan, X. et al. Graded levels of GATA-1 expression modulate survival, proliferation and differentiation of erythroid progenitors. J. Biol. Chem. 280, 22385–22394 (2005). An in vitro ES cell differentiation system was used to prove integrated function of GATA1.
Suwabe, N., Takahashi, S., Nakano, T. & Yamamoto, M. GATA-1 regulates growth and differentiation of definitive erythroid lineage cells during in vitro ES cell differentiation. Blood 92, 4108–4118 (1998).
Wieser, R. et al. Transcription factor GATA-2 gene is located near 3q21 breakpoints in myeloid leukemia. Biochem. Biophys. Res. Commun. 273, 239–245 (2000).
Wechsler, J. et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nature Genet. 12, 1–5 (2002). The first paper demonstrating the linkage between somatic mutations in the GATA1 gene and DS–AMKL.
Greene, M. E. et al. Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome. Blood Cells Mol. Dis. 31, 351–356 (2003).
Rainis, L. et al. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102, 981–986 (2003).
Xu, G. et al. Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome. Blood 102, 2960–2968 (2003). References 48–50 show that somatic mutations of GATA1 , which result in the production of short form GATA1, are related to TMD and DS–AMKL.
Shimada, A. et al. Fetal origin of the GATA1 mutation in identical twins with transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome. Blood 103, 366 (2004).
Roizen, N. J. & Patterson, D. Down's syndrome. Lancet 361, 1281–1289 (2003).
Zipursky, A. Transient leukaemia — a benign form of leukaemia in newborn infants with trisomy 21. Br. J. Haematol. 120, 930–938 (2003).
Hitzler, J. K. & Zipursky, A. Origins of leukaemia in children with Down syndrome. Nature Rev. Cancer 5, 11–20 (2005).
Harigae, H. et al. The GATA1 mutation in an adult patient with acute megakaryoblastic leukemia not accompanying Down syndrome. Blood 103, 3242–3243 (2004).
Ahmed, M. et al. Natural history of GATA1 mutations in Down syndrome. Blood 103, 2480–2489 (2004). Sequential clinical study focused on the relationship between GATA1 mutation and history of TMD and AMKL in DS children.
Hitzler, J. K., Cheung, J., Li, Y., Scherer, S. W. & Zipursky, A. GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101, 4301–4304 (2003).
Xu, G. et al. Development of acute megakaryoblastic leukemia from a minor clone in a Down syndrome patient with clinically overt transient myeloproliferative disorder. J. Pediatr. Hematol. Oncol. 28, 696–698 (2006).
Polski, J. M. et al. Acute megakaryoblastic leukemia after transient myeloproliferative disorder with clonal karyotype evolution in a phenotypically normal neonate. J. Pediatr. Hematol. Oncol. 24, 50–54 (2002).
Cushing, T. et al. Risk for leukemia in infants without Down syndrome who have transient myeloproliferative disorder. J. Pediatr. 148, 687–689 (2006).
Adam, M. et al. Transient myeloproliferative disorder in a neonate without Down syndrome. Ann. Biol. Clin. 65, 569–573 (2007).
Dierssen, M. et al. Murine models for Down syndrome. Physiol. Behav. 73, 859–871 (2001).
Antonarakis, S. E., Lyle, R., Dermitzakis, E. T., Reymond, A. & Deutsch, S. Chromosome 21 and Down syndrome: from genomics to pathophysiology. Nature Rev. Genet. 5, 725–738 (2004).
Davisson, M. T. et al. Segmental trisomy as a mouse model for Down syndrome. Prog. Clin. Biol. Res. 384, 117–133 (1993).
Richtsmeier, J. T., Zumwalt, A., Carlson, E. J., Epstein, C. J. & Reeves, R. H. Craniofacial phenotypes in segmentally trisomic mouse models for Down syndrome. Am. J. Med. Genet. 107, 317–324 (2002).
Reeves, R. H. et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genet. 11, 177–184 (1995).
Moore, C. S. Postnatal lethality and cardiac anomalies in the Ts65Dn Down syndrome mouse model. Mamm. Genome 17, 1005–1012 (2006).
Kirsammer, G. et al. Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood 111, 767–775 (2008).
Henry, E., Walker, D., Wiedmeier, S. E. & Christensen, R. D. Hematological abnormalities during the first week of life among neonates with Down syndrome: data from a multihospital healthcare system. Am. J. Med. Genet. A 143, 42–50 (2007).
Holmes, D. K. et al. Hematopoietic progenitor cell deficiency in fetuses and children affected by Down's syndrome. Exp. Hematol. 34, 1611–1615 (2006).
Toki, T. et al. Transgenic expression of Bach1 transcription factor results in megakaryocytic impairment. Blood 105, 3100–3108 (2005).
Yokomizo, T. et al. Characterization of GATA-1+ hemangioblastic cells in the mouse embryo. EMBO J. 26, 184–196 (2007).
Kuhl, C. et al. GATA1-mediated megakaryocyte differentiation and growth control can be uncoupled and mapped to different domains in GATA1. Mol. Cell. Biol. 25, 8592–8606 (2005).
Muntean, A. G. & Crispino, J. D. Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development. Blood 106, 1223–1231 (2005).
Chang, A. N. et al. GATA-factor dependence of the multitype zinc-finger protein FOG-1 for its essential role in megakaryopoiesis. Proc. Natl Acad. Sci. USA 99, 9237–9242 (2002).
Shimizu, R., Ohneda, K., Engel, J. D., Trainor, C. D. & Yamamoto, M. Transgenic rescue of GATA-1-deficient mice with GATA-1 lacking a FOG-1 association site phenocopies patients with X-linked thrombocytopenia. Blood 103, 2560–2567 (2004).
Isaacs, H. Jr. Fetal and neonatal leukemia. J. Pediatr. Hematol. Oncol. 25, 348–361 (2003).
Li, Z. et al. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nature Genet. 37, 613–619 (2005).
Hemminki, K., Lorenzo Bermejo, J. & Forsti, A. The balance between heritable and environmental aetiology of human disease. Nature Rev. Genet. 7, 958–965 (2006).
Yamamoto, M. et al. Activity and tissue-specific expression of the transcription factor NF-E1 multigene family. Genes Dev. 4, 1650–1662 (1990).
Suzuki, N. et al. Combinatorial Gata2 and Sca1 expression defines hematopoietic stem cells in the bone marrow niche. Proc. Natl Acad. Sci. USA 103, 2202–2207 (2006).
Khandekar, M. et al. A Gata2 intronic enhancer confers its pan-endothelia-specific regulation. Development 139, 1703–1712 (2007).
Pandolfi, P. P. et al. Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nature Genet. 11, 40–44 (1995).
Lowry, J. A. & Mackay, J. P. GATA-1: one protein, many partners. Int. J. Biochem. Cell Biol. 38, 6–11 (2006).
Trainor, C. D., Ghirlando, R. & Simpson, M. A. GATA zinc finger interactions modulate DNA binding and transactivation. J. Biol. Chem. 275, 28157–28166 (2000).
Trainor, C. D. et al. A palindromic regulatory site within vertebrate GATA-1 promoters requires both zinc fingers of the GATA-1 DNA-binding domain for high- affinity interaction. Mol. Cell. Biol. 16, 2238–2247 (1996).
Grass, J. A. et al. GATA-1-dependent transcriptional repression of GATA-2 via disruption of positive autoregulation and domain-wide chromatin remodeling. Proc. Natl Acad. Sci. USA 100, 8811–8816 (2003).
Kobayashi-Osaki, M. et al. GATA motifs regulate early hematopoietic lineage-specific expression of Gata2 gene. Mol. Cell. Biol. 25, 7005–7020 (2005).
Socolovsky, M. et al. Ineffective erythropoiesis in Stat5a−/−5b−/− mice due to decreased survival of early erythroblasts. Blood 98, 3261–3273 (2001).
Sposi, N. M. et al. Mechanisms of differential transferrin receptor expression in normal hematopoiesis. Eur. J. Biochem. 267, 6762–6774 (2000).
Loken, M. R., Shah, V. O., Dattilio, K. L. & Civin, C. I. Flow cytometric analysis of human bone marrow: I. Normal erythroid development. Blood 69, 255–263 (1987).
Kina, T. et al. The monoclonal antibody TER-119 recognizes a molecule associated with glycophorin A and specifically marks the late stages of murine erythroid lineage. Br. J. Haematol. 109, 280–287 (2000).
Onodera, K. et al. Conserved structure, regulatory elements, and transcriptional regulation from the GATA-1 gene testis promoter. J. Biochem. 121, 251–263 (1997).
Acknowledgements
We would like to thank K. Abe, X. Pan, T. Kuroha and S. Takahashi for discussions and comments, and E. Kobayashi and Y. Kikuchi for their help. This work is supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (R.S. and M.Y.), Japan Science and Technology Corporation–ERATO Environmental Response Project (M.Y.), and the National Institutes of Health (J.D.E.).
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transient myeloproliferative disorder
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Glossary
- Thrombocytopenia
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A severe reduction in the number of platelets circulating in the blood.
- Thalassaemia
-
An inherited autosomal recessive blood disease caused by impaired synthesis of one or more globin polypeptide chains.
- Porphyria
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Disorders caused by reduction of enzymatic activity in the porphyrin biosynthetic pathway, leading to the accumulation of porphyrin precursors.
- Haploinsufficiency
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A condition in which one copy of a diploid gene is inactivated, and the other functional copy of the gene does not produce a sufficient amount of gene product for normal cell function.
- FAB
-
The French–American–British classification system. Acute myeloid leukaemias are divided into 8 subtypes, M0 through to M7, on the basis of bone marrow and peripheral blood features.
- Hydrops fetalis
-
A serious fetal condition characterized by the abnormal accumulation of fluid in subcutaneous tissues and body cavities, often resulting as a consequence of α-globin gene deletion.
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Shimizu, R., Engel, J. & Yamamoto, M. GATA1-related leukaemias. Nat Rev Cancer 8, 279–287 (2008). https://doi.org/10.1038/nrc2348
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DOI: https://doi.org/10.1038/nrc2348
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