t(X;17)(p11;q21) BCOR/RARA

2012-01-01   Yukiya Yamamoto  

1.Department of Hematology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan

Clinics and Pathology

Disease

A variant case of acute promyelocytic leukemia

Epidemiology

Very rare. One case has been reported.

Clinics

A bone marrow sample was markedly hypercellular, containing 83% promyelocytes. Coagulopathy was present with an increased prothrombin time, an activated partial thromboplastin time, decreased fibrinogen, and mildly increased fibrin/fibrinogen degradation products.
Atlas Image
Rectangular cytoplasmic bodies and round inclusions are found in some of hypergranular promyelocytes. May-Giemsa staining.

Cytology

Bone marrow promyelocytes were strongly positive for Sudan black B, myeloperoxidase staining and naphthol AS-D chloroacetate staining and negative for alpha-naphthyl butyrate staining. Flow cytometric analysis: HLA-DR-/CD13+/CD33+/CD56+.

Treatment

Conventional chemotherapy plus ATRA achieved complete remission, followed with consolidation therapies. However, 35 months after diagnosis, the patient relapsed and cord blood transplantation was performed with a myeloablative conditioning regimen. After engraftment was achieved, a bone marrow sample showed third CR. The patient demonstrated overt coagulopathy, sensitivity to ATRA, but resistance to arsenic trioxide.

Cytogenetics

Atlas Image
FISH analysis (Vysis LSI PML/RARA dual color, dual fusion translocation probe, Vysis; Downers Grove, IL). One of the RARA signals (green) is split. PML signals (red) are intact.

Genes Involved and Proteins

Gene name
BCOR (BCL6 corepressor)
Location
Xp11.4
Protein description
The BCL6 co-repressor, BCOR, is a ubiquitously expressed nuclear protein which directly interfaces to proto-oncoprotein BCL6. BCOR also associates with HDACs, the polycomb group protein PCGF1/NSPC1 and the histone demethylase FBXL10, which implies that it could suppress gene transcription by epigenetic mechanisms.
Gene name
RARA (Retinoic acid receptor, alpha)
Location
17q21.2
Protein description
Wide expression; nuclear receptor; binds specific DNA sequences: HRE (hormone response elements); ligand and dimerization domain; role in growth and differentiation.

Result of the Chromosomal Anomaly

Atlas Image
Schematic diagram of RARA, BCOR and the BCOR-RARA fusion protein. The break point is indicated by the black line. Ankyrin repeats (ANK).

Transcript

BCOR cDNA (isoform b; reference NM_001123384) from exons 1 to 12 to be fused to RARA exon 3. Full length chimeric fusion transcripts spanning from the start codon to 4948 nt of BCOR cDNA fused to RARA cDNA from exon 3 to the stop codon. A reciprocal chimeric cDNA of RARA-BCOR was not detected.

Description

BCOR-RARA had a BCORBBD (498~514 aa), three Ankyrin repeats (1410~1509 aa) of BCOR, a DNA binding domain (DBD) derived from RARA (1557~1622 aa) and a ligand binding domain of RARA (1669~1888 aa).

Expression localisation

BCOR-RARA localized as two patterns; (I) diffusely in the nucleus as well as PML-RARA, (II) diffusely in the nucleus and aggregately in the cytoplasm. The subcellular localization of BCOR-RARA was clearly distinguishable from the punctuate pattern shown in the nucleus of BCOR-expressing cells.

Oncogenesis

BCOR-RARA was found to possess common features with other RARA fusion proteins. These included: (I) the same break point in RARA cDNA; (II) self-association; (III) RXRA is necessary for BCOR-RARA to associate with the RARA responsive element; (IV) action in a dominant-negative manner on RARA transcriptional activation; (V) aberrant subcellular relocalization.

Highly cited references

Pubmed IDYearTitleCitations
208078882010BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia.49
257909012015Successful treatment of acute promyelocytic leukemia with a t(X;17)(p11.4;q21) and BCOR-RARA fusion gene.12

Article Bibliography

Pubmed IDLast YearTitleAuthors
208078882010BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia.Yamamoto Y et al

Summary

Fusion gene

BCOR/RARA BCOR (Xp11.4) RARA (17q21.2) M t(X;17)(p11;q21)|BCOR/RARA BCOR (Xp11.4) RARA (17q21.2) TIC
Atlas Image
t(X;17)(p11;q12), G-banding.

Citation

Yukiya Yamamoto

t(X;17)(p11;q21) BCOR/RARA

Atlas Genet Cytogenet Oncol Haematol. 2012-01-01

Online version: http://atlasgeneticsoncology.org/haematological/1594/css/lib/gene-explorer/js/web-card-haematological.js