Cancer Genetics
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(2015)
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LETTER TO THE EDITOR
Successful treatment of acute promyelocytic leukemia with a t(X;17)(p11.4;q21) and BCOR-RARA fusion gene
Variant fusion genes containing retinoic acid receptor alpha (RARA) are sometimes associated with acute promyelocytic leukemia (APL). A 71-year-old man experiencing anorexia for 1 month presented with leukocytosis in April 2013. At presentation, he had leukocytosis and anemia. His platelet count was normal, and coagulopathy was trivial. A bone marrow smear showed a hypercellular marrow with marked proliferation of abnormal large myeloid cells, which were strongly positive for myeloperoxidase staining and had abundant cytoplasmic granules. Auer bodies were observed only sporadically, and there were no faggot cells. Nuclear dysplasia was not conspicuous. Flow cytometry (FCM) showed that they were CD13þ, CD33þ, HLA-DR, CD34, CD56, and CD11c. The FCM findings were typical, but the morphological findings were not characteristic of APL; therefore, a diagnosis of AML rather than APL was made. We began induction chemotherapy with idarubicin and cytarabine, which led to hematological complete remission (CR) after 4 weeks. A chromosomal analysis of bone marrow cells at presentation indicated a karyotype of 45,Y,t(X;17)(p11.4;q21), which suggested a variant fusion gene containing RARA. With reference to a previous report of APL with a t(X;17) chromosomal translocation (1), we performed PCR and DNA sequencing for the BCOR-RARA fusion gene. We detected the BCOR-RARA fusion gene, in which exon 12 of BCOR was fused with exon 3 of RARA. Hence, we made a diagnosis of variant APL. Thereafter, we performed three courses of consolidation chemotherapy combined with alltrans retinoic acid (ATRA), and molecular CR has since been maintained for a year. BCOR is a ubiquitously expressed nuclear protein and interacts with the proto-oncogene BCL6. Moreover, BCOR can associate with histone deacetylases (2), the Polycomb group protein (3), and others, and it could suppress gene transcription by epigenetic mechanisms. Recently, the BCOR gene was reported to be associated with myeloid malignancies (4,5). These observations suggest that BCOR dysfunction may be associated with the pathogenesis of myeloid malignancies. APL with BCOR-RARA has been reported only once previously (1). Yamamoto et al. reported that leukemic promyelocytes in their case had peculiar crystallized cytoplasmic bodies and round-shaped inclusion bodies. The leukemic cells in the present case did not show such peculiar 2210-7762/$ - see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2015.01.008
morphology. On the other hand, the regularly shaped nucleus and cytoplasm less granular than that of classical APL were consistent with the previous report. On FCM analysis, leukemic cells were shown to be strongly positive for CD13, CD33, and CD56 and weakly positive for CD11c in the previous case; however, in the present case, leukemic cells were negative for CD56 and CD11c. These partial inconsistencies may be affected by the differences in the fusion point of the BCOR gene; 54 bps of the C-terminus of BCOR exon 12 were deleted in the fusion transcript in our case. With respect to clinical course, the previous patient (1) was treated with ATRA-containing chemotherapy and achieved CR. Arsenic trioxide was ineffective and tamibarotene was partially effective for the relapsed disease. In this case, ATRA was also effective and has achieved and maintained CR for more than 1 year after diagnosis; however, special attention should be paid for disease relapse.
Acknowledgment Drs. Fujiwara and Harigae have received a research grant from Chugai Pharmaceutical Co., Ltd.
References 1. Yamamoto Y, Tsuzuki S, Tsuzuki M, et al. BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11; q12) variant of acute promyelocytic leukemia. Blood 2010;116: 4274e4283. 2. Huynh KD, Fischle W, Verdin E, et al. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev 2000;14: 1810e1823. 3. Gearhart MD, Corcoran CM, Wamstad JA, et al. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol Cell Biol 2006;26: 6880e6889. 4. Grossmann V, Tiacci E, Holmes AB, et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood 2011;118: 6153e6163. 5. Damm F, Chesnais V, Nagata Y, et al. BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders. Blood 2013;122:3169e3177.
Satoshi Ichikawa* Department of Hematology, Osaki Citizen Hospital Osaki, Japan
2
Letter to the Editor Department of Hematology and Rheumatology Tohoku University Graduate School of Medicine Sendai, Japan
Taro Takahashi Department of Hematology, Osaki Citizen Hospital Osaki, Japan
Sonoko Ichikawa Department of Hematology, Osaki Citizen Hospital Osaki, Japan Department of Medical Oncology, Osaki Citizen Hospital Osaki, Japan
Tohru Fujiwara Hideo Harigae Department of Hematology and Rheumatology Tohoku University Graduate School of Medicine Sendai, Japan Department of Molecular Hematology/Oncology Tohoku University Graduate School of Medicine Sendai, Japan *Corresponding author. E-mail address: [email protected]
Izumi Ishikawa Department of Hematology, Osaki Citizen Hospital Osaki, Japan Department of Internal Medicine, JR Sendai Hospital Sendai, Japan
-
(2015)
-
LETTER TO THE EDITOR
Successful treatment of acute promyelocytic leukemia with a t(X;17)(p11.4;q21) and BCOR-RARA fusion gene
Variant fusion genes containing retinoic acid receptor alpha (RARA) are sometimes associated with acute promyelocytic leukemia (APL). A 71-year-old man experiencing anorexia for 1 month presented with leukocytosis in April 2013. At presentation, he had leukocytosis and anemia. His platelet count was normal, and coagulopathy was trivial. A bone marrow smear showed a hypercellular marrow with marked proliferation of abnormal large myeloid cells, which were strongly positive for myeloperoxidase staining and had abundant cytoplasmic granules. Auer bodies were observed only sporadically, and there were no faggot cells. Nuclear dysplasia was not conspicuous. Flow cytometry (FCM) showed that they were CD13þ, CD33þ, HLA-DR, CD34, CD56, and CD11c. The FCM findings were typical, but the morphological findings were not characteristic of APL; therefore, a diagnosis of AML rather than APL was made. We began induction chemotherapy with idarubicin and cytarabine, which led to hematological complete remission (CR) after 4 weeks. A chromosomal analysis of bone marrow cells at presentation indicated a karyotype of 45,Y,t(X;17)(p11.4;q21), which suggested a variant fusion gene containing RARA. With reference to a previous report of APL with a t(X;17) chromosomal translocation (1), we performed PCR and DNA sequencing for the BCOR-RARA fusion gene. We detected the BCOR-RARA fusion gene, in which exon 12 of BCOR was fused with exon 3 of RARA. Hence, we made a diagnosis of variant APL. Thereafter, we performed three courses of consolidation chemotherapy combined with alltrans retinoic acid (ATRA), and molecular CR has since been maintained for a year. BCOR is a ubiquitously expressed nuclear protein and interacts with the proto-oncogene BCL6. Moreover, BCOR can associate with histone deacetylases (2), the Polycomb group protein (3), and others, and it could suppress gene transcription by epigenetic mechanisms. Recently, the BCOR gene was reported to be associated with myeloid malignancies (4,5). These observations suggest that BCOR dysfunction may be associated with the pathogenesis of myeloid malignancies. APL with BCOR-RARA has been reported only once previously (1). Yamamoto et al. reported that leukemic promyelocytes in their case had peculiar crystallized cytoplasmic bodies and round-shaped inclusion bodies. The leukemic cells in the present case did not show such peculiar 2210-7762/$ - see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2015.01.008
morphology. On the other hand, the regularly shaped nucleus and cytoplasm less granular than that of classical APL were consistent with the previous report. On FCM analysis, leukemic cells were shown to be strongly positive for CD13, CD33, and CD56 and weakly positive for CD11c in the previous case; however, in the present case, leukemic cells were negative for CD56 and CD11c. These partial inconsistencies may be affected by the differences in the fusion point of the BCOR gene; 54 bps of the C-terminus of BCOR exon 12 were deleted in the fusion transcript in our case. With respect to clinical course, the previous patient (1) was treated with ATRA-containing chemotherapy and achieved CR. Arsenic trioxide was ineffective and tamibarotene was partially effective for the relapsed disease. In this case, ATRA was also effective and has achieved and maintained CR for more than 1 year after diagnosis; however, special attention should be paid for disease relapse.
Acknowledgment Drs. Fujiwara and Harigae have received a research grant from Chugai Pharmaceutical Co., Ltd.
References 1. Yamamoto Y, Tsuzuki S, Tsuzuki M, et al. BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11; q12) variant of acute promyelocytic leukemia. Blood 2010;116: 4274e4283. 2. Huynh KD, Fischle W, Verdin E, et al. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev 2000;14: 1810e1823. 3. Gearhart MD, Corcoran CM, Wamstad JA, et al. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol Cell Biol 2006;26: 6880e6889. 4. Grossmann V, Tiacci E, Holmes AB, et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood 2011;118: 6153e6163. 5. Damm F, Chesnais V, Nagata Y, et al. BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders. Blood 2013;122:3169e3177.
Satoshi Ichikawa* Department of Hematology, Osaki Citizen Hospital Osaki, Japan
2
Letter to the Editor Department of Hematology and Rheumatology Tohoku University Graduate School of Medicine Sendai, Japan
Taro Takahashi Department of Hematology, Osaki Citizen Hospital Osaki, Japan
Sonoko Ichikawa Department of Hematology, Osaki Citizen Hospital Osaki, Japan Department of Medical Oncology, Osaki Citizen Hospital Osaki, Japan
Tohru Fujiwara Hideo Harigae Department of Hematology and Rheumatology Tohoku University Graduate School of Medicine Sendai, Japan Department of Molecular Hematology/Oncology Tohoku University Graduate School of Medicine Sendai, Japan *Corresponding author. E-mail address: [email protected]
Izumi Ishikawa Department of Hematology, Osaki Citizen Hospital Osaki, Japan Department of Internal Medicine, JR Sendai Hospital Sendai, Japan
