Toggle Main Menu Toggle Search

Open Access padlockePrints

Hyperactive CREB subpopulations increase during therapy in pediatric B-lineage acute lymphoblastic leukemia

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.

Publication metadata

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


DOI: 10.3324/haematol.2022.281177

PubMed id: 36420798


Altmetrics provided by Altmetric