6533b7d9fe1ef96bd126b965
RESEARCH PRODUCT
Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1
Carmen D. HerlingDavide RossiF. Thomas WunderlichMarek FranitzaHans Christian ReinhardtRiccardo MoiaPhilipp LohneisRenzo BoldoriniRenzo BoldoriniWolfram KlapperMarco HerlingReinhard BüttnerElena HartmannChristian P. PallaschMilos NikolicGero KnittelJens C. BrüningNadine NickelMartin PeiferNina ReinartTheodoros GeorgomonolisMarcus KrügerA. RothStephan C. SchäferStuart BlakemoreAndreas RosenwaldNadine HövelmeyerMartin PalJanica L WiedersteinLukas P. FrenzelVivien KohlhaasMichael HallekMona Al-maarriGianluca Gaidanosubject
0301 basic medicineTumor microenvironmentChronic lymphocytic leukemiaImmunologyNotch signaling pathwayMedizinAggressive lymphomaCell BiologyHematologyBiologymedicine.diseaseBiochemistrySomatic evolution in cancerLymphoma03 medical and health sciencesLeukemia030104 developmental biology0302 clinical medicineimmune system diseaseshemic and lymphatic diseasesmedicineCancer researchneoplasmsProtein kinase B030215 immunologydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-02-04 |