Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1
- 4 February 2021
- journal article
- Published by American Society of Hematology in Blood
- Vol. 137 (5), 646-660
- https://doi.org/10.1182/blood.2020005734
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.Keywords
This publication has 56 references indexed in Scilit:
- EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemiaLeukemia, 2016
- Richter transformation of CLLExpert Review of Hematology, 2016
- Richter syndrome: pathogenesis and managementSeminars in Oncology, 2016
- The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergyHaematologica, 2014
- How we treat Richter syndromeBlood, 2014
- Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndromeThe Journal of Experimental Medicine, 2013
- B-cell receptor signaling in chronic lymphocytic leukemiaBlood, 2011
- The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformationBlood, 2011
- Stereotyped B-Cell Receptor Is an Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter SyndromeClinical Cancer Research, 2009
- Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndromeBritish Journal of Haematology, 2008