RTP801 is a novel retinoic acid–responsive gene associated with myeloid differentiation

Gery, Sigal; Park, Dorothy J.; Vuong, Peter T.; Virk, Renu K.; Muller, Claudia I.; Hofmann, Wolf-K.; Koeffler, H. Phillip

doi:10.1016/j.exphem.2007.01.049

« Previous Next »Experimental Hematology
Volume 35, Issue 4 , Pages 572-578, April 2007

RTP801 is a novel retinoic acid–responsive gene associated with myeloid differentiation

Sigal Gery
- Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, Calif., USA
- Offprint requests to: Sigal Gery, PhD, Cedars-Sinai Medical Center, Davis Bldg. 5066, 8700 Beverly Blvd., Los Angeles, CA 90048
- These authors contributed equally to the manuscript.
Dorothy J. Park
- Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, Calif., USA
- These authors contributed equally to the manuscript.
Peter T. Vuong
- Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, Calif., USA
Renu K. Virk
- Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, Calif., USA
Claudia I. Muller
- Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, Calif., USA
Wolf-K. Hofmann
- Department of Hematology and Oncology and Transfusion Medicine, University Hospital “Benjamin Franklin,” Berlin, Germany
H. Phillip Koeffler
- Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, Calif., USA

Received 24 November 2006; received in revised form 20 January 2007; accepted 22 January 2007.

Objective

Retinoids are crucial in the regulation of fundamental cellular processes including terminal differentiation of both normal and malignant myeloid progenitors. The aim of this study was to identify and characterize retinoic acid (RA) target genes.

Methods and Results

RTP801 is a recently cloned stress response gene that acts as a negative regulator of the mTOR pathway. Here we identified RTP801 as a novel early RA target gene in myeloid cells. RTP801 mRNA levels are induced in acute myeloid leukemia (AML) cell lines during RA-dependent differentiation and are differentially expressed during maturation of normal CD34⁺ cells. The myeloid-specific, differentiation-related transcription factor C/EBPɛ also induces RTP801 expression. Overexpression of RTP801 in the U937 leukemic cells leads to growth inhibition and apoptosis. Conversely, silencing of endogenous RTP801 by shRNA reduces RA-induced differentiation of the U937 cells. Downregulation of RTP801 also abrogates hypoxia-induced inhibition of mTOR in those cells.

Conclusion

Taken together, our data suggest that RTP801 is an important RA-regulated gene involved in myeloid differentiation, which could represent a therapeutic target in leukemia.