NCOA3, a new fusion partner for MOZ/MYST3 in M5 acute myeloid leukemia

The recurrent translocation t(8;16)(p11;p13) is found in about 6.5% of acute myeloid leukemias (AMLs) of the M4/M5-FAB subtypes. These poor prognosis AMLs are associated with erythrophagocytosis by blast cells. The translocation results in the fusion of the MYST3 gene (also known as MOZ) on chromosome region 8p11 to the CREBBP gene (also known as CBP) on chromosome region 16p13.1, 2, 3 In the same type of AML, the t(10;16)(q22;p13) fuses MYST3-homolog MYST4 to CREBBP4 and the t(8;22)(p11;q13) fuses MYST3 to CREBBP-homolog EP300.5 MYST3, MYST4, CREBBP and EP300 encode transcriptional regulators and acetyltransferases. MYST3 is also fused to NCOA2 in the inv(8)(p11q13).6, 7 NCOA1/SRC1, NCOA2/TIF2 and NCOA3 are paralogous genes encoding transcription coactivators of the p160 family.8 Some rearrangements involving NCOA genes and MYST3 or MYST4 genes have not been reported yet, but have been suspected or predicted on the basis of homology relations.4 We report here a new type of translocation, t(8;20)(p11;q13), which occurs in an M5-AML and fuses MYST3 to NCOA3.

The patient, a 75-year-old woman, presented in September 2006 with fever, dyspnea, bruises, splenomegaly and disseminated intravascular coagulation. White blood cell count was 67.5 × 109 l−1, hemoglobin level 11 g dl−1 and platelet count 45 × 109 l−1. Bone marrow (BM) examination showed 91% blast cells of AML-M5 type without the features of erythrophagocytosis. Cytogenetic analysis of BM cells showed a t(8;20)(p11;q13) in 18 mitoses among the 23 analyzed (Figure 1a). The patient was treated with hydroxyurea followed by low-dose cytosine arabinoside. Remission was not obtained and the patient died in December 2006 of intracerebral hemorrhage.

Figure 1
figure1

Characterization of MYST3–NCOA3 fusion in patient cells with t(8;20)(p11;q13). (a) RHG and GTG-banded partial karyotypes showing the t(8;20)(p11;q13) in bone marrow (BM) cells of the patient. Arrows indicate the cytogenetic location of 8p11 and 20q13 breakpoints on the derivative chromosomes. (b) FISH of metaphase chromosomes of t(8;20)(p11;q13) BM cells with digoxigenin-labeled RP11-313J18 (MYST3 at 8p11, revealed in red, TRITC) and biotinylated RP11-1151C1 (5′ and main part of NCOA3 region at 20q13, revealed in green, FITC) and RP11-122N8 (3′ part of NCOA3 and SULF2 region at 20q13, revealed in green, FITC). Genomic information was taken from the UCSC Genome Browser on Human, March 2006 Assembly, based on NCBI Build 36.1 (National Center for Biotechnology Information, Bethesda, MD 20894) (http://genome.ucsc.edu/). BACs were obtained from the BACPAC resource (Children's Hospital Oakland, BACPAC Resources, Oakland, CA, USA). Fused RP11-313J18/RP11-1151C1+RP11-122N8 (red/green) signals observed on der(8) and der(20) chromosomes suggest that the t(8;20) translocation affects MYST3 and NCOA3 loci. (c) Detection of fusion transcripts by RT-PCR analysis. The MYST3–NCOA3 and its reciprocal fusion transcripts are detected in the patient's BM cells, with respective 345 and 419 bp amplified fragments visualized on agarose gel with ethidium bromide. cDNA from normal lymphocytes were used as control. Primers specific for the NMA gene were used for the control of RT-PCR efficiency. (d) Schematic representation of the putative MYST3–NCOA3 fusion protein with its functional domains and motifs, defined according to the SMART program (http://smart.embl-heidelberg.de/) and after the manual alignment of NCOA proteins. MYST3 and NCOA3 sequences (Ensembl Transcript ID ENST00000265713 and ENST00000262979) are from Ensembl database (http://www.ensembl.org/Homo_sapiens/). Nucleotide (cDNA level) and deduced amino-acid sequences of MYST3–NCOA3 are positioned above and below the corresponding putative fusion protein, respectively. CID:CREB-interacting domain. (e) Schematic MYST and MLL recombinome. Translocations known to target NCOA, MYST and MLL genes in AML and t-MDS and corresponding fusion proteins are indicated. MYST partners are CREB-binding proteins. The MYST3-NCOA1 in a t(2;8) has been suspected but not characterized.4

Based on hematology (FAB subtype) and homology,4 we suspected the involvement of MYST3 and NCOA3 in the translocation. We demonstrated the involvement of these loci by using dual-color fluorescence in situ hybridization (FISH) on metaphases of AML-BM cells, using labeled-BAC clones, as previously described4, 7 (Figure 1b). The MYST3–NCOA3 gene fusion was confirmed by using PCR amplification of retrotranscribed mRNA from BM cells of the patient, as previously described.7 The two wild-type and the two fusion transcripts were amplified (Figure 1c) using MYST3 and NCOA3 primer sequences (available on demand). The breakpoint in MYST3 occurs in intron-17, as in MYST3–CREBBP (type I) and MYST3–NCOA2.3, 6 The breakpoint in NCOA3 is located at nucleotides 2752 and 2376 in the MYST3–NCOA3 and NCOA3–MYST3 fusion transcripts, respectively. It occurs in exon 13, which is truncated of 45 base pairs. Only the MYST3–NCOA3 fusion transcript has an open reading frame that may generate a functional chimeric protein. As in MYST3–NCOA2, the CREB-interacting domain in NCOA3 (1046–1092 aa) is conserved in the putative MYST3–NCOA3 fusion protein (at positions 1246–1292 aa) suggesting a similar potential oncogenic role in targeting the transcription machinery in AML-M4/M5 involving MYST3, MYST4 or MLL fusions (Figure 1d).

Thus, NCOA3 is a new fusion partner for MYST3. The presence of t(8;20)(p11;q13) in an M4 or M5-AML should lead to search for a MYST3–NCOA3 fusion. However, the event must be rare since the Mitelman database (http://cgap.nci.nih.gov/Chromosomes/Mitelman) does not indicate the recurrence. Fusion between NCOA and MYST4 genes has not been observed yet (Figure 1e). MYST3 and MYST4 fusions are hybrid regulators of transcription. NCOA3 has connection with several signaling pathways involved in oncogenesis and may be a therapeutic target.

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Acknowledgements

This work was supported by Inserm and Institut Paoli-Calmettes.

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Correspondence to M-J Mozziconacci.

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Esteyries, S., Perot, C., Adelaide, J. et al. NCOA3, a new fusion partner for MOZ/MYST3 in M5 acute myeloid leukemia. Leukemia 22, 663–665 (2008). https://doi.org/10.1038/sj.leu.2404930

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