Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia

Higuchi, Masakazu; O'Brien, Darin P.; Kumaravelu, Parasakthy; Lenny, Noel; Yeoh, Allen Eng Juh; Downing, James R.

doi:10.1016/s1535-6108(02)00016-8

Cited by 410 publications

(399 citation statements)

References 41 publications

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“…However, no disease was developed in EHKI DNeo mice during the long-term observation period (Figure 2a, thin lines), indicating that the acquired expression of E2A-HLF per se is insufficient for the development of leukemia. This finding is in line with previous reports showing that iKI mice of other leukemogenic transcription factor chimeras, such as AML1-ETO and MLL-CBP, did not show hematopoietic disorders, and secondary mutations induced by N-methyl-N-nitrosourea or irradiation were required to induce a fully malignant phenotype (Higuchi et al, 2002;Wang et al, 2005). In this study, to introduce additional gene alterations, we used RIM, as it not only …”

Section: Discussionsupporting

confidence: 85%

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

et al. 2010

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E2A-hepatic leukemia factor (HLF) is a chimeric protein found in B-lineage acute lymphoblastic leukemia (ALL) with t(17;19). To analyze the leukemogenic process and to create model mice for t(17;19)-positive leukemia, we generated inducible knock-in (iKI) mice for E2A-HLF. Despite the induced expression of E2A-HLF in the hematopoietic tissues, no disease was developed during the long observation period, indicating that additional gene alterations are required to develop leukemia. To elucidate this process, E2A-HLF iKI and control littermates were subjected to retroviral insertional mutagenesis. Virus infection induced acute leukemias in E2A-HLF iKI mice with higher morbidity and mortality than in control mice. Inverse PCR detected three common integration sites specific for E2A-HLF iKI leukemic mice, which induced overexpression of zinc-finger transcription factors: growth factor independent 1 (Gfi1), zinc-finger protein subfamily 1A1 isoform a (Zfp1a1, also known as Ikaros) and zinc-finger protein 521 (Zfp521). Interestingly, tumors with Zfp521 integration exclusively showed B-lineage ALL, which corresponds to the phenotype of human t(17;19)-positive leukemia. In addition, ZNF521 (human counterpart of Zfp521) was found to be overexpressed in human leukemic cell lines harboring t(17;19). Moreover, both iKI for E2A-HLF and transgenic for Zfp521 mice frequently developed B-lineage ALL. These results indicate that a set of transcription factors promote leukemic transformation of E2A-HLF-expressing hematopoietic progenitors and suggest that aberrant expression of Zfp521/ZNF521 may be clinically relevant to t(17;19)-positive B-lineage ALL.

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Section: Discussionsupporting

confidence: 85%

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

et al. 2010

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“…It may be a common underlying mechanism for the pathogenesis in AML1-associated leukemia. However, recently generated transgenic or knock-in mice showed that AML1 mutations are critical for the development of AML, but that one or more additional mutations are necessary for leukemogenesis [10][11][12]. This accepted hypothesis is supported by the cytogenetic findings in the case of our patient exhibiting a complex karyotype.…”

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confidence: 69%

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene

et al. 2009

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“…, 2004). RUNX1-ETO expression in conjunction with treatment with the mutagen N-ethyl-N-nitrosourea (ENU) resulted in myeloid leukemia or granulocytic sarcoma (Yuan et al, 2001;Higuchi et al, 2002). Therefore, RUNX1-ETO is able to predispose myeloid precursors to transformation.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

et al. 2006

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The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.

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Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia

Cited by 410 publications

References 41 publications

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

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