| 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.
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| 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.
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