Fusion AML1 transcript in a radiation-associated leukemia results in a truncated inhibitory AML1 protein

Hromas, Robert; Busse, Tracey; Carroll, Audra L.; Mack, David L.; Shopnick, Rinah; Zhang, Dong Er; Nakshatri, Harikrishna; Richkind, Kathleen E.

doi:10.1182/blood.v97.7.2168

Cited by 34 publications

(30 citation statements)

References 10 publications

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“…One of these, isolated from a radiation-associated secondary AML, fused the N-terminal AML1 DNA-binding domain out of frame to AMP19, which resulted in a truncated AML1 protein that inhibited activation of a myeloidspecific promoter by CBF. 6 Another of these out-of-frame AML1 fusions was found in a myelodysplasia bearing a t(3;21). 5 This fused the N-terminal AML1 DNA-binding domain out of frame to EAP, also resulting in a truncated inhibitory AML1 protein.…”

Section: To the Editormentioning

confidence: 99%

“…The other two are AML1 -EAP, and AML1-AMP19. 4,6 All these three cases with the truncated AML1 species had elements hematopoietic dysplasia. These truncated AML1 species likely played a role in the myelodysplastic phenotype seen in each of these cases, by inhibiting the normal CBF activation of myeloid-specific genes.…”

Section: To the Editormentioning

confidence: 99%

“…1,2 However, there have been several recent reports of AML1 translocations involving other partner genes. [3][4][5][6] These other translocations involving AML1 are fairly rare. In general, these have usually occurred in secondary leukemias.…”

Section: To the Editormentioning

confidence: 99%

“…Using RACE PCR, 6 the partner gene in this translocation was cloned and found to be a previously undescribed member of the copine family we termed copine VIII (GenBank # AY177785, mouse homologue AK004559). The 5' telomeric portion (DNA-binding domain) of AML1 was broken after exon 6 and fused to the intron 2 sequence from the Copine VIII gene (Figure 1b), near the amino terminus of the protein.…”

Section: To the Editormentioning

confidence: 99%

“…1,2,4,6 This hypothesis was tested using cotransfection assays with the M-CSF receptor promoter as a reporter as we described. 6 The M-CSF receptor is a known target for activation by CBF. The cotransfection assays found that CBF activation of the M-CSF receptor promoter was inhibited up to 3.4-fold by AML1-Copine VIII (Figure 3).…”

Section: To the Editormentioning

confidence: 99%

See 4 more Smart Citations

Fusion of AML1/Runx1 to Copine VIII, a novel member of the copine family, in an aggressive acute myelogenous leukemia with t(12;21) translocation

Ramsey

Zhang

Richkind³

et al. 2003

Leukemia

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Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

See 3 more Smart Citations

Fusion of AML1/Runx1 to Copine VIII, a novel member of the copine family, in an aggressive acute myelogenous leukemia with t(12;21) translocation

Ramsey

Zhang

Richkind³

et al. 2003

Leukemia

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21q22 balanced chromosome aberrations in therapy‐related hematopoietic disorders: Report from an International Workshop†

Slovak

Bedell

Popplewell

et al. 2002

Genes Chromosomes & Cancer

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The International Workshop on the relationship between prior therapy and balanced chromosome aberrations in therapy-related myelodysplastic syndromes (t-MDS) and therapy-related acute leukemia (t-AL) identified 79 of 511 (15.5%) patients with balanced 21q22 translocations. Patients were treated for their primary disease, including solid tumors (56%), hematologic malignancy (43%), and juvenile rheumatoid arthritis (single case), by radiation therapy (5 patients), chemotherapy (36 patients), or combined-modality therapy (38 patients). 21q translocations involved common partner chromosomes in 81% of cases: t(8;21) (n = 44; 56%), t(3;21) (n = 16; 20%), and t(16;21) (n = 4; 5%). Translocations involving 15 other partner chromosomes were also documented with involvement of AML1(CBFA2/RUNX1), identifying a total of 23 different 21q22/AML1 translocations. The data analysis was carried out on the basis of five subsets of 21q22 cases, that is, t(8;21) with and without additional aberrations, t(3;21), t(16;21), and other 21q22 translocations. Dysplastic features were present in all 21q22 cases. Therapy-related acute myeloid leukemia (t-AML) at presentation was highest in t(8;21) (82%) and lowest in t(3;21) (37.5%) patients. Cumulative drug dose exposure scores for alkylating agents (AAs) and topoisomerase II inhibitors indicated that t(3;21) patients received the most intensive therapy among the five 21q22 subsets, and the median AA score for patients with secondary chromosome 7 aberrations was double the AA score for the entire 21q22 group. All five patients who received only radiation therapy had t(8;21) t-AML. The median latency and overall survival (OS) for 21q22 patients were 39 and 14 months (mo), compared to 26 and 8 mo for 11q23 patients, 22 and 28 mo for inv(16), 69 and 7 mo for Rare recurring aberrations, and 59 and 7 mo for Unique (nonrecurring) balanced aberration (latency P < or = 0.016 for all pairwise comparisons; OS, P < or = 0.018 for all pairwise comparisons). The percentages of 21q22 patients surviving 1 year, 2 years, and 5 years were 58%, 33%, and 18%, respectively. Noticeable differences were observed in median OS between 21q22 patients (n = 7) receiving transplant (BMT) (31 mo) compared to 21q22 patients who received intensive non-BMT therapy (n = 46) (17 mo); however, this was nonsignificant because of the small sample size (log-rank, P = 0.33). t-MDS/t-AML with balanced 21q22 aberrations was associated with prior exposure to radiation, epipodophyllotoxins, and anthracyclines, dysplastic morphologic features, multiple partner chromosomes, and longer latency periods when compared to 11q23 and inv(16) t-MDS/AML Workshop subgroups. In general, patients could be divided into two prognostic risk groups, those with t(8;21) (median OS, 19 mo) and those without t(8;21) (median OS, 7 mo) leukemia (log-rank, P = 0.0007).

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Novel RUNX1‐PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22)

Sakai

Tamura

Narumi

et al. 2005

Genes Chromosomes & Cancer

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The t(1;21)(p36;q22) is a recurrent chromosome abnormality associated with therapy-related acute myeloid leukemia (AML). Although involvement of RUNX1 has been detected by fluorescence in situ hybridization analysis, the partner gene has not been reported previously. We identified a novel RUNX1 partner gene, MDS1/EVI1-like-gene 1 (PRDM16), in an AML patient with t(1;21). Alternative splicing of the fusion gene generates five different fusion transcripts. In two of them, the PRDM16 reading frame is maintained in the fusion with RUNX1, suggesting that the RUNX1-PRDM16 gene fusion results in the production of a protein that is highly homologous to the RUNX1-MDS1/EVI1 chimeric protein. It is suggested that PRDM16 and MDS1/EVI1 share a common molecular mechanism for the leukemogenesis of RUNX1-associated leukemia. Characterization of the RUNX1-PRDM16 fusion protein and comparison with the RUNX1-MDS1/EVI1 protein will facilitate the understanding of the mechanisms underlying RUNX1-associated leukemia.

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Fusion AML1 transcript in a radiation-associated leukemia results in a truncated inhibitory AML1 protein

Cited by 34 publications

References 10 publications

Fusion of AML1/Runx1 to Copine VIII, a novel member of the copine family, in an aggressive acute myelogenous leukemia with t(12;21) translocation

Fusion of AML1/Runx1 to Copine VIII, a novel member of the copine family, in an aggressive acute myelogenous leukemia with t(12;21) translocation

21q22 balanced chromosome aberrations in therapy‐related hematopoietic disorders: Report from an International Workshop†

Novel RUNX1‐PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22)

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