Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Author:

Jin Qi12ORCID,Gutierrez Diaz Blanca12ORCID,Pieters Tim345ORCID,Zhou Yalu12,Narang Sonali678ORCID,Fijalkwoski Igor345ORCID,Borin Cristina345ORCID,Van Laere Jolien34,Payton Monique9ORCID,Cho Byoung-Kyu10ORCID,Han Cuijuan12ORCID,Sun Limin12ORCID,Serafin Valentina1112ORCID,Yacu George1,Von Loocke Wouter6ORCID,Basso Giuseppe1112,Veltri Giulia11ORCID,Dreveny Ingrid13ORCID,Ben-Sahra Issam12ORCID,Goo Young Ah1210,Safgren Stephanie L.14ORCID,Tsai Yi-Chien15,Bornhauser Beat15ORCID,Suraneni Praveen Kumar16,Gaspar-Maia Alexandre14ORCID,Kandela Irawati17,Van Vlierberghe Pieter345ORCID,Crispino John D.9,Tsirigos Aristotelis678ORCID,Ntziachristos Panagiotis345ORCID

Affiliation:

1. Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.

2. Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

3. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.

4. Center for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium.

5. Cancer Research Institute Ghent (CRIG), Ghent, Belgium.

6. Department of Pathology, New York University School of Medicine, New York, NY, USA.

7. Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.

8. Applied Bioinformatics Laboratories, Office of Science and Research, New York University School of Medicine, New York, NY, USA.

9. Division of Experimental Hematology, St. Jude Children’s Research Hospital, Memphis, TN, USA.

10. Proteomics Center of Excellence, Northwestern University, Evanston, IL, USA.

11. Oncohematology Laboratory, Department of Women’s and Children’s Health, University of Padova, Padova, Italy.

12. Department of Surgery Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova, Padova, Italy.

13. School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.

14. Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

15. University Children’s Hospital, Division of Pediatric Oncology, University of Zurich, Zurich, Switzerland.

16. Department of Cell and Developmental Biology, Northwestern University, Chicago, IL, USA.

17. Center for Developmental Therapeutics, Northwestern University, Evanston, IL, USA.

Abstract

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell–specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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