NOTCH1 dimeric signaling is essential for T-cell leukemogenesis and leukemia maintenance
Abstract
Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that is characterized by an expansion of T-cell progenitors and DNA mutations that lead to overactive NOTCH1 signaling in >50% of T-ALL cases. Using synthetic models of human T-ALL, we report that NOTCH1 dimeric signaling was crucial for the leukemogenesis of human hematopoietic stem/progenitor cells (HSPCs) from cord blood. We also identified a Notch dimerization–dependent gene signature, including the HES4 transcription factor, which induced a proliferative advantage in human HSPCs and in Notch dimerization–dependent, patient-derived xenografts of T-ALL. Interestingly, in human T-ALL cells, HES4 enforced the expression of the Δ133p53 isoform with the concomitant block of proapoptotic p53 target genes and the induction of BCL2L1 gene expression and antiapoptotic B-cell lymphoma extra-large protein. In addition, through an integrated experimental approach that included genetically modified cell lines, RNA/chromatin immunoprecipitation sequencing, and single-cell RNA sequencing profiles of primary T-ALL samples, we revealed cell subsets with Notch dimerization–dependent gene signatures, which indirectly correlated with proapoptotic genes and directly associated with cell markers of poor clinical outcome in primary T-ALL samples. Taken together, these findings highlight the crucial role of NOTCH1 dimeric signaling in human T-cell leukemogenesis and T-ALL maintenance, suggesting that a possible benefit can be obtained with a therapeutic strategy that target NOTCH1 dimer signaling or its downstream effectors.
Article Details
Authors (15)
Francesco Tamiro
1Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Costanzo Padovano
1Fondazione IRCCS Casa Sollievo della Sofferenza, Institute of Regenerative Medicine (ISBReMIT), San Giovanni Rotondo, Italy
Elisabetta De Santis
1Fondazione IRCCS Casa Sollievo della Sofferenza, Institute of Regenerative Medicine (ISBReMIT), San Giovanni Rotondo, Italy
Serena Di Iasio
1Fondazione IRCCS Casa Sollievo della Sofferenza, Institute of Regenerative Medicine (ISBReMIT), San Giovanni Rotondo, Italy
Delia Francesca Sansico
1Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Valentina Canistro
1Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Mattia Colucci
1Fondazione IRCCS Casa Sollievo della Sofferenza, Institute of Regenerative Medicine (ISBReMIT), San Giovanni Rotondo, Italy
Chiara Di Nunzio
1Fondazione IRCCS Casa Sollievo della Sofferenza, Institute of Regenerative Medicine (ISBReMIT), San Giovanni Rotondo, Italy
Gaja Bruno
1Fondazione IRCCS Casa Sollievo della Sofferenza, Institute of Regenerative Medicine (ISBReMIT), San Giovanni Rotondo, Italy
Kashish Doshi
3Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC, Canada
Angela Totaro
4Cord Blood Bank, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Eric Gu
3Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC, Canada
Michele Santodirocco
4Cord Blood Bank, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Andrew P. Weng
3Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC, Canada
Vincenzo Giambra
1Fondazione IRCCS Casa Sollievo della Sofferenza, Institute of Regenerative Medicine (ISBReMIT), San Giovanni Rotondo, Italy