A case of AML characterized by a novel t(4;15)(q31;q22) translocation that confers a growth-stimulatory response to retinoid-based therapy

Justin Watts, Aymee Perez, Lutecia Pereira, Yao-Shan Fan, Geoffrey Brown, Francisco Vega, Kevin Petrie, Ronan T Swords, Arthur Z Zelent

Research output: Contribution to journalArticle

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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 RAR 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.

Original languageEnglish (US)
Article number1492
JournalInternational Journal of Molecular Sciences
Volume18
Issue number7
DOIs
StatePublished - Jul 11 2017

Fingerprint

leukemias
Retinoids
Tretinoin
Acute Myeloid Leukemia
therapy
acids
Acids
Growth
Fusion reactions
fusion
cells
Therapeutics
Investigational Therapies
biomarkers
Biomarkers
Myeloid Cells
RNA
Karyotype
progressions
genes

Keywords

  • Acute myeloid leukemia
  • ATRA
  • NCT02273102
  • Retinoid
  • T(4; 15)(q31; Q22)
  • TMEM154-RASGRF1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

A case of AML characterized by a novel t(4;15)(q31;q22) translocation that confers a growth-stimulatory response to retinoid-based therapy. / Watts, Justin; Perez, Aymee; Pereira, Lutecia; Fan, Yao-Shan; Brown, Geoffrey; Vega, Francisco; Petrie, Kevin; Swords, Ronan T; Zelent, Arthur Z.

In: International Journal of Molecular Sciences, Vol. 18, No. 7, 1492, 11.07.2017.

Research output: Contribution to journalArticle

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