한빛사논문
- 조회2,337
Harvard Medical School, Massachusetts General Hospital, Harvard University
Sooncheol Lee1,2,3,4, Douglas Micalizzi1,2, Samuel S. Truesdell1,3,4, Syed I. A. Bukhari1,2,3,4, Myriam Boukhali1,2, Jennifer Lombardi-Story1,2, Yasutaka Kato5, Min-Kyung Choo6, Ipsita Dey-Guha1,2, Fei Ji7, Benjamin T. Nicholson1, David T. Myers1, Dongjun Lee8, Maria A. Mazzola9, Radhika Raheja9, Adam Langenbucher1,10, Nicholas J. Haradhvala1,10,11, Michael S. Lawrence1,10,11, Roopali Gandhi9, Christopher Tiedje12, Manuel D. Diaz-Muñoz13, David A. Sweetser1,14, Ruslan Sadreyev7,10, David Sykes2,3,4, Wilhelm Haas1,2, Daniel A. Haber1,2,15, Shyamala Maheswaran1,16 and Shobha Vasudevan1,2,3,4,*
1 Massachusetts General Hospital Cancer Center, Harvard Medical School, 185 Cambridge St, CPZN4202, Boston, MA 02114, USA.
2 Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, Massachusetts, USA.
3 Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
4 Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
5 Laboratory of Oncology, Hokuto Hospital, Obihiro, Japan.
6 Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
7 Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
8 Department of Convergence Medical Science, Pusan National University School of Medicine, Yangsan 506121257-1258South Korea.
9 Center for Neurological Diseases, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
10 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
11 Broad Institute of Harvard & MIT, Cambridge, MA 02142, USA.
12 Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
13 Centre de Physiopathologie Toulouse-Purpan, INSERM UMR1043/CNRS U5282, Toulouse, France.
14 Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
15 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
16 Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown,MA 02129, USA.
* Correspondence : Shobha Vasudevan
Abstract
Background
Quiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown.
Results
We induce chemoresistant and G0 leukemic cells by serum starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the upregulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, Tristetraprolin (TTP) in G0. This permits expression of ARE mRNAs that promote chemoresistance. Conversely, inhibition of TTP phosphorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE-bearing TNFα and DUSP1 mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNFα prior to or along with chemotherapy substantially reduces chemoresistance in primary leukemic cells ex vivo and in vivo.
Conclusions
These studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE-bearing mRNAs that promote chemoresistance. By disrupting this pathway, we develop an effective combination therapy against chemosurvival.
논문정보
- Research article
- 2020년 02월 (BRIC 등록일 2020-02-19)
- 국외 연구진
- 생명과학 > 노화/암생물학
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