American Association for Cancer Research
00085472can181703-sup-202976_2_supp_5036744_pf7spm.xlsx (269.25 kB)

Supplementary Data from CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia

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posted on 2023-03-31, 02:06 authored by Jesús Duque-Afonso, Chiou-Hong Lin, Kyuho Han, David W. Morgens, Edwin E. Jeng, Ziming Weng, Johan Jeong, Stephen Hon Kit Wong, Li Zhu, Michael C. Wei, Hee-Don Chae, Martin Schrappe, Gunnar Cario, Justus Duyster, Xiangshu Xiao, Kathleen M. Sakamoto, Michael C. Bassik, Michael L. Cleary

Unbiased shRNA library screening and global transcriptome analyses reveal mechanisms that modulate dasatinib sensitivity and suggest therapeutic strategies to improve outcome of patients with acute lymphoblastic leukemia.



William Lawrence and Blanche Hughes Foundation

German Research Foundation

Research Commission of the University of Freiburg

Lucile Packard Foundation for Children's Health, the Child Health Research Institute


Alex's Lemonade Stand Foundation for Childhood Cancer

The Walter V. and Idun Berry Postdoctoral Fellowship

Leukemia and Lymphoma Society of America

Pediatric Cancer Research Foundation

St. Baldrick's Foundation

Bear Necessities/Rally Foundation

Hubert Shaw and Sandra Lui Stanford

National Science Foundation



Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional coactivator CBP increased dasatinib sensitivity by downregulating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due, in part, to upregulation of alternative pathways including WNT through a mechanism, suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR+ ALL, which can be reversed by small-molecule inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL.Significance: These findings reveal mechanisms that modulate sensitivity to dasatinib and suggest therapeutic strategies to improve the outcome of patients with acute lymphoblastic leukemia.Graphical Abstract: Cancer Res; 78(22); 6497–508. ©2018 AACR.

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