Identification and characterization of novel AML1-ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: a report from the Children's Oncology Group

LaFiura, Katherine M.; Edwards, Holly; Taub, Jeffrey W.; Matherly, Larry H.; Fontana, Joseph A.; Mohamed, Anwar N.; Ravindranath, Yaddanapudi

doi:10.1038/onc.2008.134

Cited by 15 publications

(14 citation statements)

References 29 publications

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“…Here, we report for the first time that the plus/minus exon 9a ratio in FTs is significantly higher than in native transcripts ( P < 0.001). Given the fact that several splice variants have been reported to be present in RUNX1‐RUNX1T1 patient cells (14) one might speculate whether this extends to other RUNX1‐RUNX1T1 FT splice variants. However, while our data demonstrate that an altered balance in alternative splicing is operative in most RUNX1‐RUNX1T1 + patients, one of the patients with normal diagnosis splice variant ratio had persistently normal ratio both during therapy and at relapse (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Persistent altered fusion transcript splicing identifies RUNX1‐RUNX1T1+ AML patients likely to relapse

Ommen

Østergaard

Yan

et al. 2010

European J of Haematology

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In acute myeloid leukemia (AML) mouse models, the RUNX1-RUNX1T1 fusion protein has failed to produce leukemia by itself, but alternative splicing of exon 9a of the RUNX1-RUNX1T1 fusion transcript (FT) has recently been shown to enhance the leukemogenic potential. We have analyzed 138 diagnosis and follow-up samples from 13 RUNX1-RUNX1T1+ patients as well as diagnosis samples from 13 RUNX1-RUNX1T1- AML patients and 26 healthy donors. Levels of native RUNX1T1 mRNA were low in both healthy and RUNX1-RUNX1T1-negative AML samples. Likewise, the ratio between RUNX1T1 mRNA harboring exon 9a and lacking exon 9a was low and tightly regulated (0.017-0.11). In contrast, 11/13 RUNX1-RUNX1T1-positive AML patients displayed high and variable ratios of FT ranging from 0.05 to 0.46 (P < 0.001, Wilcoxon rank-sum test), indicating altered exon 9a splicing in these patients. Importantly, patients who remained in continuous complete remission displayed a faster disappearance of the RUNX1-RUNX1T1 exon 9a splice variant compared to patients bound to relapse (P = 0.02). In conclusion, alternative splicing seems to be part of the leukemogenic process in the majority of RUNX1-RUNX1T1-positive AML patients, and splice variant kinetics under cytoreduction may be a predictor for patients prone to relapse.

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Section: Discussionmentioning

confidence: 99%

Persistent altered fusion transcript splicing identifies RUNX1‐RUNX1T1+ AML patients likely to relapse

Ommen

Østergaard

Yan

et al. 2010

European J of Haematology

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“…Interestingly, several studies have demonstrated a wide range of variant protein‐coding and noncoding transcripts generated from the RUNX1‐RUNX1T1 gene related to the utilization of different RUNX1 promoters and alternative RUNX1T1 exons (Era et al, ; Erickson et al, ; Kozu, Fukuyama, Yamami, Akagi, & Kaneko, ; Kozu et al, ; LaFiura et al, ; Mannari, Gascoyne, Dunne, Chaplin, & Young, ; M. Yan et al, ). The breakpoints in the RUNX1 gene cluster in intron 5 and the breakpoints in RUNX1T1 cluster in intron 1.…”

Section: Oncogenic Fusion Transcripts—partners In Cancermentioning

confidence: 99%

Fusion transcripts: Unexploited vulnerabilities in cancer?

2019

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Gene fusions are an important class of mutations in several cancer types and include genomic rearrangements that fuse regulatory or coding elements from two different genes. Analysis of the genetics of cancers harboring fusion oncogenes and the proteins they encode have enhanced cancer diagnosis and in some cases patient treatment. However, the effect of the complex structure of fusion genes on the biogenesis of the resulting chimeric transcripts they express is not well studied. There are two potential RNA‐related vulnerabilities inherent to fusion‐driven cancers: (a) the processing of the fusion precursor messenger RNA (pre‐mRNA) to the mature mRNA and (b) the mature mRNA. In this study, we discuss the effects that the genetic organization of fusion oncogenes has on the generation of translatable mature RNAs and the diversity of fusion transcripts expressed in different cancer subtypes, which can fundamentally influence both tumorigenesis and treatment. We also discuss functional genomic approaches that can be utilized to identify proteins that mediate the processing of fusion pre‐mRNAs. Furthermore, we assert that an enhanced understanding of fusion transcript biogenesis and the diversity of the chimeric RNAs present in fusion‐driven cancers will increase the likelihood of successful application of RNA‐based therapies in this class of tumors.This article is categorized under:RNA Processing > RNA Editing and ModificationRNA Processing > Splicing Regulation/Alternative SplicingRNA in Disease and Development > RNA in Disease

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“…Several in-frame variants of these forms have been identified, and their final effects on the expression of AML1 responsive genes seem to vary from repressive to activating [65]. …”

Section: Molecular Genetics Of T(8;21)mentioning

confidence: 99%

Acute Myeloid Leukemia with the t(8;21) Translocation: Clinical Consequences and Biological Implications

Reikvam

Hatfield

Kittang

et al. 2011

BioMed Research International

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The t(8;21) abnormality occurs in a minority of acute myeloid leukemia (AML) patients. The translocation results in an in-frame fusion of two genes, resulting in a fusion protein of one N-terminal domain from the AML1 gene and four C-terminal domains from the ETO gene. This protein has multiple effects on the regulation of the proliferation, the differentiation, and the viability of leukemic cells. The translocation can be detected as the only genetic abnormality or as part of more complex abnormalities. If t(8;21) is detected in a patient with bone marrow pathology, the diagnosis AML can be made based on this abnormality alone. t(8;21) is usually associated with a good prognosis. Whether the detection of the fusion gene can be used for evaluation of minimal residual disease and risk of leukemia relapse remains to be clarified. To conclude, detection of t(8;21) is essential for optimal handling of these patients as it has both diagnostic, prognostic, and therapeutic implications.

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Identification and characterization of novel AML1-ETO fusion transcripts in pediatric t(8;21) acute myeloid leukemia: a report from the Children's Oncology Group

Cited by 15 publications

References 29 publications

Persistent altered fusion transcript splicing identifies RUNX1‐RUNX1T1+ AML patients likely to relapse

Persistent altered fusion transcript splicing identifies RUNX1‐RUNX1T1+ AML patients likely to relapse

Fusion transcripts: Unexploited vulnerabilities in cancer?

Acute Myeloid Leukemia with the t(8;21) Translocation: Clinical Consequences and Biological Implications

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