Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1

Author:

Kohlhaas Vivien12345,Blakemore Stuart James346ORCID,Al-Maarri Mona12345,Nickel Nadine346,Pal Martin12345,Roth Andreas346,Hövelmeyer Nadine7,Schäfer Stephan C.8ORCID,Knittel Gero346,Lohneis Philipp8,Nikolic Milos49,Wiederstein Janica L.39,Franitza Marek10,Georgomonolis Theodoros1011ORCID,Reinart Nina346,Herling Marco346,Herling Carmen346,Hartmann Elena M.12,Rosenwald Andreas12,Klapper Wolfram13ORCID,Büttner Reinhard8,Moia Riccardo14,Rossi Davide1516,Boldorini Renzo1417,Gaidano Gianluca17,Frenzel Lukas P.346,Reinhardt Hans Christian34618,Brüning Jens C.12345,Hallek Michael346,Krüger Marcus39,Peifer Martin49ORCID,Pallasch Christian P.346ORCID,Wunderlich F. Thomas12345ORCID

Affiliation:

1. Max Planck Institute for Metabolism Research, Cologne, Germany;

2. Institute for Genetics, University of Cologne, Cologne, Germany;

3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany;

4. Center for Molecular Medicine Cologne (CMMC), Cologne, Germany;

5. Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, Cologne, Germany;

6. Department I of Internal Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany;

7. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany;

8. Institute of Pathology,

9. Department of Translational Genomics, and

10. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany;

11. West German Genome Center (WGGC), Cologne, Germany;

12. Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany;

13. Department of Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany;

14. Division of Pathology, Department of Health Science, University of Piemonte Orientale (UPO), Novara, Italy;

15. Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;

16. Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland;

17. Università del Piemonte Orientale, Department of Translational Medicine, Novara, Italy; and

18. Clinic for Hematology and Stem Cell Transplant, University Hospital of Essen, Essen, Germany

Abstract

Abstract Richter’s transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase–associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and diffuse large B-cell lymphoma. Multiomics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed an S100 protein-defined subcluster of highly aggressive lymphoma cells that developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation toward aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference58 articles.

1. Generalized reticular cell sarcoma of lymph nodes associated with lymphatic leukemia;Richter;Am J Pathol,1928

2. Richter syndrome: pathogenesis and management;Rossi;Semin Oncol,2016

3. Richter transformation of CLL;Jain;Expert Rev Hematol,2016

4. How we treat Richter syndrome;Parikh;Blood,2014

5. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome;Fabbri;J Exp Med,2013

Cited by 61 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3