Runx3 is required for hematopoietic development in zebrafish

Kalev‐Zylinska, Maggie L.; Horsfield, Julia A.; Flores, Maria Vega; Postlethwait, John H.; Chau, Jackie Y. M.; Cattin, Peter M.; Vitas, Maria R.; Crosier, Philip S.; Crosier, Kathryn E.

doi:10.1002/dvdy.10388

Cited by 60 publications

(51 citation statements)

References 77 publications

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“…Transgenic mice expressing AML1͞ETO, either from the MRP8 promoter (13) or by using a tetracycline-inducible system (15), have no detectable in vivo hematopoietic phenotype. Finally, transient expression of an AML1͞ETO transgene in zebrafish embryos caused vascular abnormalities and dysplastic myeloid and erythroid differentiation (36). Taken together, these results support the notion that AML1͞ ETO expression is not sufficient to induce leukemia but suggest that differences in the cellular compartment expressing AML1͞ETO or differences in the transgene dose may be critical determinants for the capacity of AML1͞ETO to alter hematopoiesis.…”

Section: Discussionsupporting

confidence: 58%

Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice

Fenske

Pengue²,

Mathews³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The t(8;21)(q22;q22) translocation, present in 10 -15% of acute myeloid leukemia (AML) cases, generates the AML1͞ETO fusion protein.To study the role of AML1͞ETO in the pathogenesis of AML, we used the Ly6A locus that encodes the well characterized hematopoietic stem cell marker, Sca1, to target expression of AML1͞ETO to the hematopoietic stem cell compartment in mice. Whereas germ-line expression of AML1͞ETO from the AML1 promoter results in embryonic lethality, heterozygous Sca1 ؉/AML1-ETO ires EGFP (abbreviated Sca ؉/AE ) mutant mice are born in Mendelian ratios with no apparent abnormalities in growth or fertility. Hematopoietic cells from Sca ؉/AE mice have markedly extended survival in vitro and increasing myeloid clonogenic progenitor output over time. Sca ؉/AE mice develop a spontaneous myeloproliferative disorder with a latency of 6 months and a penetrance of 82% at 14 months. These results reinforce the notion that the phenotype of murine transgenic models of human leukemia is critically dependent on the cellular compartment targeted by the transgene. This model should provide a useful platform to analyze the effect of AML1͞ETO on hematopoiesis and its potential cooperation with other mutations in the pathogenesis of leukemia.T he t(8;21)(q22;q22) translocation is one of the most commonly detected karyotypic abnormalities in acute myeloid leukemia (AML). This genetic alteration is found in up to 40% of de novo AML cases of the French-American-British M2 subtype, and in 12-15% of AML cases overall (1, 2). In many instances of AML, t(8;21) is the sole cytogenetic abnormality, suggesting that the translocation plays a key role in transformation. The t(8;21) translocation fuses sequences from the AML1 (RUNX1, CBFA2, and PEBP␣) gene on chromosome 21 to the ETO (MTG8) gene on chromosome 8. This translocation results in production of the AML1͞ETO protein, an in-frame fusion of the N terminus of AML1 and virtually the entire ETO protein. AML1 is the DNAbinding subunit of core-binding factor (CBF), a multimeric transcription factor complex that includes CBF␤ and additional transcriptional coactivators. Mice lacking either Aml1 or Cbf␤ fail to develop definitive intraembryonic hematopoiesis and die midgestation (3-6). Mice heterozygous for an AML1͞ETO allele knocked into the Aml1 locus have an identical phenotype, providing genetic evidence that the AML1͞ETO fusion protein acts as a dominant inhibitor of CBF activity (7,8).Although it is clear that CBF plays a critical role in hematopoietic development, several lines of evidence suggest that expression of its dominant inhibitor AML1͞ETO is not sufficient to cause AML. AML1͞ETO expression is frequently detectable in peripheral blood cells from t(8;21) AML patients for years into durable remission (9, 10). Conversely, clonotypic AML1͞ETO sequences were identified in DNA retrospectively extracted from neonatal blood samples from 5 of 10 children with t(8;21) AML, preceding the development of AML by 5-10 years in these cases (11). Several strains of AML1͞ETO-express...

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Section: Discussionsupporting

confidence: 58%

Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice

Fenske

Pengue²,

Mathews³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…We have previously reported embryonic expression of zebrafish runx3 in neuronal and hematopoietic tissues (Kalev-Zylinska et al, 2003). Here, we examined the pattern of runx3 expression in the pharyngeal region.…”

Section: Zebrafish Runx3 Is Expressed Early In the Pharyngeal Endodermmentioning

confidence: 97%

“…Zebrafish larvae are viable without blood supply for the first week of development, providing an opportunity to analyse the outcome of events such as Runx1 depletion, which are embryonic-lethal in mammals. We have previously cloned the zebrafish orthologs for all Runx genes (KalevZylinska et al, 2002;Kalev-Zylinska et al, 2003;Flores et al, 2004). In zebrafish, runx2 is duplicated (Flores et al, 2004), but not runx1 or runx3.…”

Section: Introductionmentioning

confidence: 99%

A hierarchy of Runx transcription factors modulate the onset of chondrogenesis in craniofacial endochondral bones in zebrafish

Flores

Lam

Crosier

et al. 2006

Developmental Dynamics

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The Runx (runt-related) family of transcription factors are important regulators of cell fate decisions in early embryonic development, and in differentiation of tissues including blood, neurons, and bone. During skeletal development in mammals, while only Runx2 is essential for osteoblast differentiation, all family members seem to be involved in chondrogenesis. Runx2 and Runx3 control chondrocyte maturation. Both Runx1 and Runx2 are expressed early in mesenchymal condensations, but how they contribute to the initial stages of chondrocyte differentiation is unclear. Here we show that a hierarchy of Runx transcriptional regulation promotes the early program of chondrocyte differentiation from pre-cartilage mesenchyme in the zebrafish head skeleton. We have previously characterized the zebrafish orthologs for all Runx genes. Zebrafish runx2 is duplicated, but not runx1 or runx3. In the work presented here, we determined the early expression pattern of the runx genes in the craniofacial region. The earliest expression detected was that of runx3 in the pharyngeal endoderm, then runx2a and b in mesenchymal condensations, and later runx1 in the epithelium. Using antisense morpholino knockdown analysis, we examined their respective activities in early chondrogenesis. Depletion of runx2b (but not runx2a) and runx3 severely compromised craniofacial cartilage formation. Because runx2b expression was abolished in Runx3 morphants, we propose that endodermal Runx3 has a role in influencing signaling activities from the endoderm to promote chondrocyte differentiation. We also show that, in contrast to data from mouse studies, zebrafish Runx1 is not required in the initial steps of chondrogenesis leading to endochondral bone formation. Developmental Dynamics 235:3166 -3176, 2006.

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“…This has led to a search for the relevant second (or third or fourth) hits, primarily focused on using mouse models. Other models are also being used including human and zebrafish, as expression of AML1-ETO in zebrafish leads to the abnormal proliferation of early, dysplastic appearing hematopoietic progenitor cells (Kalev-Zylinska et al, 2002), and the zebrafish represents a powerful genetic system to search for second hits.…”

Section: Second Hitsmentioning

confidence: 99%

Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells

Nimer

Moore

2004

Oncogene

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Runx3 is required for hematopoietic development in zebrafish

Abstract: We cloned zebrafish runx3/aml2/cbfa3 and examined its expression and function during embryogenesis. In the developing embryo, runx3 is dynamically expressed in hematopoietic, neuronal, and cartilaginous tissues.

Cited by 60 publications

References 77 publications

Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice

Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice

A hierarchy of Runx transcription factors modulate the onset of chondrogenesis in craniofacial endochondral bones in zebrafish

Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells

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