論文 - 詳細
| RRC ID | 57656 |
|---|---|
| 著者 | Osumi T, Tsujimoto SI, Tamura M, Uchiyama M, Nakabayashi K, Okamura K, Yoshida M, Tomizawa D, Watanabe A, Takahashi H, Hori T, Yamamoto S, Hamamoto K, Migita M, Ogata-Kawata H, Uchiyama T, Kizawa H, Ueno-Yokohata H, Shirai R, Seki M, Ohki K, Takita J, Inukai T, Ogawa S, Kitamura T, Matsumoto K, Hata K, Kiyokawa N, Goyama S, Kato M. |
| タイトル | Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation. |
| ジャーナル | Cancer Res |
| Abstract |
Translocations of retinoic acid receptor-α (RARA), typically PML-RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1-RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, TBL1XR1-RARB homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. TBL1XR1-RARB enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as PML-RARA did. However, the response of APL with RARB translocation to retinoids was attenuated compared with that of PML-RARA, an observation in line with the clinical resistance of RARB-positive APL to ATRA. Our results demonstrate that the majority of RARA-negative APL have RARB translocations, thereby forming a novel, distinct subgroup of APL. TBL1XR1-RARB as an oncogenic protein exerts effects similar to those of PML-RARA, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL.Significance: These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. Cancer Res; 78(16); 4452-8. ©2018 AACR. |
| 巻・号 | 78(16) |
| ページ | 4452-4458 |
| 公開日 | 2018-8-15 |
| DOI | 10.1158/0008-5472.CAN-18-0840 |
| PII | 0008-5472.CAN-18-0840 |
| PMID | 29921692 |
| MeSH | Animals Bone Marrow Cells / metabolism Bone Marrow Cells / pathology Humans Leukemia, Promyelocytic, Acute / genetics* Leukemia, Promyelocytic, Acute / pathology Mice Nuclear Proteins / genetics Oncogene Proteins, Fusion / genetics Receptors, Cytoplasmic and Nuclear / genetics Receptors, Retinoic Acid / genetics* Repressor Proteins / genetics Retinoic Acid Receptor alpha / genetics* Signal Transduction / genetics Translocation, Genetic* Tretinoin / metabolism Whole Genome Sequencing |
| IF | 9.727 |
| 引用数 | 12 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 研究用ヒト臍帯血幹細胞 | |