TY - JOUR
T1 - Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1
AU - Kohlhaas, Vivien
AU - Blakemore, Stuart James
AU - Al-Maarri, Mona
AU - Nickel, Nadine
AU - Pal, Martin
AU - Roth, Andreas
AU - Hövelmeyer, Nadine
AU - Schäfer, Stephan C.
AU - Knittel, Gero
AU - Lohneis, Philipp
AU - Nikolic, Milos
AU - Wiederstein, Janica L.
AU - Franitza, Marek
AU - Georgomonolis, Theodoros
AU - Reinart, Nina
AU - Herling, Marco
AU - Herling, Carmen
AU - Hartmann, Elena M.
AU - Rosenwald, Andreas
AU - Klapper, Wolfram
AU - Büttner, Reinhard
AU - Moia, Riccardo
AU - Rossi, Davide
AU - Boldorini, Renzo
AU - Gaidano, Gianluca
AU - Frenzel, Lukas P.
AU - Reinhardt, Hans Christian
AU - Brüning, Jens C.
AU - Hallek, Michael
AU - Krüger, Marcus
AU - Peifer, Martin
AU - Pallasch, Christian P.
AU - Wunderlich, F. Thomas
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/2/4
Y1 - 2021/2/4
N2 - 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. Key Points: • Constitutively active AKT is present in high-risk CLL and RT, and active Akt transforms murine CLL toward aggressive lymphoma. • Akt orchestrates development of RT via induction of Notch1 signaling in B cells, fueled by Dll1-expressing T cells.
AB - 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. Key Points: • Constitutively active AKT is present in high-risk CLL and RT, and active Akt transforms murine CLL toward aggressive lymphoma. • Akt orchestrates development of RT via induction of Notch1 signaling in B cells, fueled by Dll1-expressing T cells.
UR - http://www.scopus.com/inward/record.url?scp=85100396783&partnerID=8YFLogxK
U2 - 10.1182/blood.2020005734
DO - 10.1182/blood.2020005734
M3 - Article
SN - 0006-4971
VL - 137
SP - 646
EP - 660
JO - Blood
JF - Blood
IS - 5
ER -