Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • RARA protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Retinoic Acid Receptor alpha
  • TBL1XR1 protein, human
  • retinoic acid receptor beta
  • Tretinoin