Ribonuclease H attack of leukaemic fused transcripts <i>AML1‐MTG8</i><i>(ETO)</i> by DNA/RNA chimeric hammerhead ribozymes

Kozu, Tomoko; Sugio, Yasuhiro; Sueoka, Eisaburo; Otsuka, Teruhisa; Akagi, Kiwamu

doi:10.1046/j.1365-2443.2000.00353.x

Cited by 3 publications

(1 citation statement)

References 43 publications

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“…However, the knockdown was not complete and ribozyme-mediated targeting of the fusion protein, as well as antisense RNA, appeared to be more effective at inducing both cellular differentiation and eventually cell death (Sakakura et al, 1994;Matsushita et al, 1995;Kozu et al, 2000;Szyrach et al, 2001). Thus, DEP may be a potent targeted therapy for t(8;21) AML as it targets multiple pathways, including reducing the levels of RUNX1-ETO.…”

Section: Runx1-eto Degradation In Response To Hdis G Yang Et Almentioning

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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Section: Runx1-eto Degradation In Response To Hdis G Yang Et Almentioning

confidence: 99%

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

et al. 2006

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Discrimination of target by siRNA: designing of AML1–MTG8 fusion mRNA-specific siRNA sequences

2004

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AML1 Interconnected Pathways of Leukemogenesis

Michaud

Scott

Escher

2003

Cancer Investigation

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The AML1 transcription factor, identified by the cloning of the translocation t(8;21) breakpoint, is one of the most frequent targets for chromosomal translocations in leukemia. Furthermore, polysomies and point mutations can also alter AML1 function. AML1, also called CBF alpha 2, PEBP alpha 2 or RUNX1, is thus implicated in a great number of acute leukemias via a variety of pathogenic mechanisms and seems to act either as an oncogene or a tumor suppressor gene. Characterization of AML1 knockout mice has shown that AML1 is necessary for normal development of all hematopoietic lineages and alterations in the overal functional level of AML1 can have a profound effect on hematopoiesis. Numerous studies have shown that AML1 plays a vital role in the regulation of expression of many genes involved in hematopoietic cell development, and the impairment of AML1 function disregulates the pathways leading to cellular proliferation and differentiation. However, heterozygous AML1 mutations alone may not be sufficient for the development of leukemia. A cumulative process of mutagenesis involving additional genetic events in functionally related molecules, may be necessary for the development of leukemia and may determine the leukemic phenotype. We review the known AML1 target genes, AML1 interacting proteins, AML1 gene alterations and their effects on AML1 function, and mutations in AML1-related genes associated with leukemia. We discuss the interconnections between all these genes in cell signaling pathways and their importance for future therapeutic developments.

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Ribonuclease H attack of leukaemic fused transcripts AML1‐MTG8(ETO) by DNA/RNA chimeric hammerhead ribozymes

Abstract: Background: Catalytic anti-sense oligonucleotides might be useful tools for controlling speci®c gene expression. However, to obtain effective oligonucleotides of the desired function in vivo is still a dif®cult task.

Cited by 3 publications

References 43 publications

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

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

Discrimination of target by siRNA: designing of AML1–MTG8 fusion mRNA-specific siRNA sequences

AML1 Interconnected Pathways of Leukemogenesis

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