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Cancer Res. 2018 Aug 15;78(16):4452-4458. doi: 10.1158/0008-5472.CAN-18-0840. Epub 2018 Jun 19.

Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation.

Author information

1
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
2
Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
3
Department of Pediatrics, Yokohama City University, Yokohama, Japan.
4
Division of Cellular Therapy, the Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
6
Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan.
7
Department of Pediatrics, Niigata Cancer Center Hospital, Niigata, Japan.
8
Department of Pediatrics, Toho University, Tokyo, Japan.
9
Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan.
10
Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.
11
Department of Pediatrics, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan.
12
Department of Pediatrics, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan.
13
Department of Human Genetics, National Research Institute for Child Health and Development, Tokyo, Japan.
14
Department of Clinical Laboratory Medicine, National Center for Child Health and Development, Tokyo, Japan.
15
Department of Pediatrics, The University of Tokyo, Tokyo, Japan.
16
Department of Pediatrics, University of Yamanashi, Chuo, Japan.
17
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
18
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan. katom-tky@umin.ac.jp.
#
Contributed equally

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.

PMID:
29921692
DOI:
10.1158/0008-5472.CAN-18-0840
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