2. Academic Validation
  3. A Case of AML Characterized by a Novel t(4;15)(q31;q22) Translocation That Confers a Growth-Stimulatory Response to Retinoid-Based Therapy

A Case of AML Characterized by a Novel t(4;15)(q31;q22) Translocation That Confers a Growth-Stimulatory Response to Retinoid-Based Therapy

  • Int J Mol Sci. 2017 Jul 11;18(7):1492. doi: 10.3390/ijms18071492.
Justin M Watts 1,  Aymee Perez 2,  Lutecia Pereira 3,  Yao-Shan Fan 4,  Geoffrey Brown 5 6,  Francisco Vega 7,  Kevin Petrie 8,  Ronan T Swords 9,  Arthur Zelent 10
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. jxw401@miami.edu.
  • 2 Division of Hematology/Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. aperez10@med.miami.edu.
  • 3 Division of Hematology/Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. lpereira@med.miami.edu.
  • 4 Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. yfan@med.miami.edu.
  • 5 Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK. g.brown@bham.ac.uk.
  • 6 Institute of Clinical Sciences, University of Birmingham, Birmingham B15 2TT, UK. g.brown@bham.ac.uk.
  • 7 Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. fvega@med.miami.edu.
  • 8 Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK. kevin.petrie@stir.ac.uk.
  • 9 Division of Hematology/Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. rswords@med.miami.edu.
  • 10 Division of Hematology/Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. a.zelent@med.miami.edu.
PMID: 28696354 DOI: 10.3390/ijms18071492
Abstract

Here we report the case of a 30-year-old woman with relapsed acute myeloid leukemia (AML) who was treated with all-trans retinoic acid (ATRA) as part of investigational therapy (NCT02273102). The patient died from rapid disease progression following eight days of continuous treatment with ATRA. Karyotype analysis and RNA-Seq revealed the presence of a novel t(4;15)(q31;q22) reciprocal translocation involving the TMEM154 and RASGRF1 genes. Analysis of primary cells from the patient revealed the expression of TMEM154-RASGRF1 mRNA and the resulting fusion protein, but no expression of the reciprocal RASGRF1-TMEM154 fusion. Consistent with the response of the patient to ATRA therapy, we observed a rapid proliferation of t(4;15) primary cells following ATRA treatment ex vivo. Preliminary characterization of the retinoid response of t(4;15) AML revealed that in stark contrast to non-t(4;15) AML, these cells proliferate in response to specific agonists of RARα and RARγ. Furthermore, we observed an increase in the levels of nuclear RARγ upon ATRA treatment. In summary, the identification of the novel t(4;15)(q31;q22) reciprocal translocation opens new avenues in the study of retinoid resistance and provides potential for a new biomarker for therapy of AML.

Keywords

15)(q31; ATRA; NCT02273102; TMEM154-RASGRF1; acute myeloid leukemia; q22); retinoid; t(4.

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