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A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia
M Carapeti1, R C Aguiar, J M Goldman
1Department of Haematology, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Abstract:
Chromosomal abnormalities of band 8p11 are associated with a distinct subtype of acute myeloid leukemia with French-American-British M4/5 morphology and prominent erythrophagocytosis by the blast cells. This subtype is usually associated with the t(8;16)(p11;p13), a translocation that has recently been shown to result in a fusion between the MOZ and CBP genes. We have cloned the inv(8)(p11q13), an abnormality associated with the same leukemia phenotype, and found a novel fusion between MOZ and the nuclear receptor transcriptional coactivator TIF2/GRIP-1/NCoA-2. This gene has not previously been implicated in the pathogenesis of leukemia or other malignancies. MOZ-TIF2 retains the histone acetyltransferase homology domains of both proteins and also the CBP binding domain of TIF2. We speculate that the apparently identical leukemia cell phenotype observed in cases with the t(8;16) and the inv(8) arises by recruitment of CBP by MOZ-TIF2, resulting in modulation of the transcriptional activity of target genes by a mechanism involving abnormal histone acetylation.
Insights
Chromosomal abnormalities involving band 8p11 link to a specific acute myeloid leukemia subtype. A novel MOZ-TIF2 gene fusion was discovered, potentially explaining leukemia development through abnormal histone acetylation.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Band 8p11 chromosomal abnormalities are linked to a specific acute myeloid leukemia (AML) subtype.
- This AML subtype exhibits French-American-British M4/5 morphology and significant erythrophagocytosis by blast cells.
- The t(8;16)(p11;p13) translocation, often associated with this AML, results in a MOZ-CBP gene fusion.
Observation:
- The inv(8)(p11q13) chromosomal abnormality, presenting with the same leukemia phenotype, was investigated.
- A novel gene fusion involving MOZ and the transcriptional coactivator TIF2 (also known as GRIP-1/NCoA-2) was identified.
- This TIF2 gene had not been previously implicated in leukemia or other cancers.
Findings:
- The resulting MOZ-TIF2 fusion protein retains key functional domains from both parent proteins.
- Specifically, it preserves the histone acetyltransferase (HAT) homology domains of MOZ and the CBP binding domain of TIF2.
- This structural characteristic suggests a potential mechanism for aberrant gene regulation.
Implications:
- The identical leukemia cell phenotype in t(8;16) and inv(8) cases may stem from MOZ-TIF2 recruiting CBP.
- This recruitment could lead to abnormal histone acetylation, modulating the transcriptional activity of target genes.
- This discovery offers new insights into the molecular pathogenesis of specific AML subtypes and potential therapeutic targets.