In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia

Wiemels, Joseph L.; Xiao, Zhijian; Buffler, Patricia A.; Maia, Ana-Teresa; Ma, Xiaomei; Dicks, Brian M.; Smith, Martyn T.; Zhang, Luoping; Feusner, James; Wiencke, John; Pritchard‐Jones, Kathy; Kempski, Helena; Greaves, Mel

doi:10.1182/blood.v99.10.3801

Cited by 250 publications

(176 citation statements)

References 29 publications

(28 reference statements)

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“…The presence of AML1-ETO mRNA in patients with long-term remission (Guerrasio et al, 1995) and in blood spots taken from identical twins (Wiemels et al, 2002) suggests that expression of AML1-ETO is not sufficient for inducing leukemia. This has led to a search for the relevant second (or third or fourth) hits, primarily focused on using mouse models.…”

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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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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“…AE transcripts have been detected in nonneoplastic progenitors from AML patients in remission, suggesting that the translocation is an early event in the leukemogenic process (4). Furthermore, t(8;21) translocation and AE expression can be detected in neonatal Guthrie blood spots, implying an in utero origin of the translocation preceding development of AML in children by as much as 10 years (5,6).Several murine models have demonstrated that AE alone is not sufficient to induce leukemia. Mice expressing an inducible AE transgene in bone marrow cells remained disease-free for a normal life span of 24 mo (7).…”

mentioning

confidence: 99%

An activated receptor tyrosine kinase, TEL/PDGFβR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice

Grisolano

O’Neal

Cain

et al. 2003

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

124

116

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The t(8;21)(q22;q22) translocation, occurring in 40% of patients with acute myeloid leukemia (AML) of the FAB-M2 subtype (AML with maturation), results in expression of the RUNX1-CBF2T1 [AML1-ETO (AE)] fusion oncogene. AML͞ETO may contribute to leukemogenesis by interacting with nuclear corepressor complexes that include histone deacetylases, which mediate the repression of target genes. However, expression of AE is not sufficient to transform primary hematopoietic cells or cause disease in animals, suggesting that additional mutations are required. Activating mutations in receptor tyrosine kinases (RTK) are present in at least 30% of patients with AML. To test the hypothesis that activating RTK mutations cooperate with AE to cause leukemia, we transplanted retrovirally transduced murine bone marrow coexpressing TEL-PDGFRB and AE into lethally irradiated syngeneic mice. These mice (19͞19, 100%) developed AML resembling M2-AML that was transplantable in secondary recipients. In contrast, control mice coexpressing with TEL-PDGFRB and a DNA-binding-mutant of AE developed a nontransplantable myeloproliferative disease identical to that induced by TEL-PDGFRB alone. We used this unique model of AML to test the efficacy of pharmacological inhibition of histone deacetylase activity by using trichostatin A and suberoylanilide hydroxamic acid alone or in combination with the tyrosine kinase inhibitor, imatinib mesylate. We found that although imatinib prolonged the survival of treated mice, histone deacetylase inhibitors provided no additional survival benefit. These data demonstrate that an activated RTK can cooperate with AE to cause AML in mice, and that this system can be used to evaluate novel therapeutic strategies.T he t(8;21)(q22;q22) translocation, which fuses the RUNX1 (AML1͞PEBP␣͞CBFA2) gene on chromosome 21 with the ETO (MTG8) gene on chromosome 8, is a common mutation associated with cases of acute myeloid leukemia (AML) of the FAB-M2 subtype (AML with maturation) (1). Expression of the resulting AML1-ETO (AE) fusion gene is detected in 40% of M2-AML patients and 12% of all newly diagnosed cases of AML (2, 3). The correlation between AE expression and the leukemic phenotype strongly suggests a causative role for AE in transformation. AE transcripts have been detected in nonneoplastic progenitors from AML patients in remission, suggesting that the translocation is an early event in the leukemogenic process (4). Furthermore, t(8;21) translocation and AE expression can be detected in neonatal Guthrie blood spots, implying an in utero origin of the translocation preceding development of AML in children by as much as 10 years (5,6).Several murine models have demonstrated that AE alone is not sufficient to induce leukemia. Mice expressing an inducible AE transgene in bone marrow cells remained disease-free for a normal life span of 24 mo (7). When expression of AE was targeted to the myeloid lineage by using the human MRP8 promoter, again the mice had no discernable phenotype (8). However, when additional random mu...

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“…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-expressing transgenic mice have been generated (12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

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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In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia

Cited by 250 publications

References 29 publications

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

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

An activated receptor tyrosine kinase, TEL/PDGFβR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice

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

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