Browse by author
Lookup NU author(s): Dr Dino Masic, Kayleigh Fee, Dr Hayden BellORCiD, Marian Case, Juan Ojeda Garcia, Dr David McDonald, Claire Schwab, Dr Frederik van DelftORCiD, Professor Andrew FilbyORCiD, Professor Julie Irving
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Persistence of residual disease in acute lymphoblastic leukemia (ALL) during the initial stages of chemotherapy is associated with inferior survival. To better understand clonal evolution and mechanisms of chemoresistance, we used multiparameter mass cytometry, at single-cell resolution, to functionally characterize pediatric B-ALL cells at disease presentation and those persisting during induction therapy. Analysis of ALL cells from presentation samples (n=42) showed that the most abundant phosphosignals were pCREB, pH2AX and pHH3 and we identified JAK-STAT and RAS pathway activation in five of six patients with JAK or RAS genetic aberrations. The clonal composition of ALL was heterogeneous and dynamic during treatment but all viable cell clusters showed pCREB activation. Levels of pCREB in ALL cells were increased or maintained during therapy and high dimensional analysis revealed a subpopulation of ALL cells at presentation that was positive for pCREB/pHH3/pS6 which increased during treatment in some patients, implicating this signaling node in conferring a survival advantage to multi-agent induction therapy. The small molecule CREB inhibitor, 666-15, was shown to reduce CREB transcriptional activity and induce apoptosis in ALL patient-derived xenograft cells of varying cytogenetic subtypes in vitro, both in the presence and absence of stromal support. Together, these data suggest that the cAMP signaling pathway may provide an opportunity for minimal residual disease-directed therapy for many patients at high risk of relapse.
Author(s): Masic D, Fee K, Bell H, Case M, Witherington G, Lansbury S, Ojeda-Garcia J, McDonald D, Schwab C, Van Delft FW, Filby A, Irving JAE
Publication type: Article
Publication status: Published
Journal: Haematologica
Year: 2023
Volume: 108
Issue: 4
Pages: 981-992
Print publication date: 01/04/2023
Online publication date: 24/11/2022
Acceptance date: 10/11/2022
Date deposited: 27/04/2023
ISSN (electronic): 1592-8721
Publisher: Fondazione Ferrata Storti
URL: https://doi.org/10.3324/haematol.2022.281177
DOI: 10.3324/haematol.2022.281177
PubMed id: 36420798
Altmetrics provided by Altmetric
