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Int. J. Mol. Sci. 2017, 18(7), 1492; doi:10.3390/ijms18071492

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

1
Division of Hematology/Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
2
Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
3
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
4
Institute of Clinical Sciences, University of Birmingham, Birmingham B15 2TT, UK
5
Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK
These authors contributed equally to this study.
*
Authors to whom correspondence should be addressed.
Received: 6 June 2017 / Revised: 4 July 2017 / Accepted: 5 July 2017 / Published: 11 July 2017
(This article belongs to the Special Issue The Biology and Treatment of Myeloid Leukaemias)
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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. View Full-Text
Keywords: acute myeloid leukemia; t(4; 15)(q31; q22); TMEM154-RASGRF1; ATRA; retinoid; NCT02273102 acute myeloid leukemia; t(4; 15)(q31; q22); TMEM154-RASGRF1; ATRA; retinoid; NCT02273102
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Watts, J.M.; Perez, A.; Pereira, L.; Fan, Y.-S.; Brown, G.; Vega, F.; Petrie, K.; Swords, R.T.; Zelent, A. 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, 18, 1492.

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