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

Publication Date:
2018-11-16
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
0008-5472
Electronic ISSN:
1538-7445
Topics:
Medicine
Published by:
http://www.aacr.org/
_version_ 1836399087028535296
autor Jesus 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
beschreibung 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: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.
citation_standardnr 6357354
datenlieferant ipn_articles
feed_id 9360
feed_publisher The American Association for Cancer Research (AACR)
feed_publisher_url http://www.aacr.org/
insertion_date 2018-11-16
journaleissn 1538-7445
journalissn 0008-5472
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association for Cancer Research (AACR)
quelle Cancer Research
relation http://cancerres.aacrjournals.org/content/78/22/6497.short?rss=1
search_space articles
shingle_author_1 Jesus 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
shingle_author_2 Jesus 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
shingle_author_3 Jesus 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
shingle_author_4 Jesus 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
shingle_catch_all_1 CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
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: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.
Jesus 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
The American Association for Cancer Research (AACR)
0008-5472
00085472
1538-7445
15387445
shingle_catch_all_2 CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
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: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.
Jesus 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
The American Association for Cancer Research (AACR)
0008-5472
00085472
1538-7445
15387445
shingle_catch_all_3 CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
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: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.
Jesus 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
The American Association for Cancer Research (AACR)
0008-5472
00085472
1538-7445
15387445
shingle_catch_all_4 CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
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: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.
Jesus 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
The American Association for Cancer Research (AACR)
0008-5472
00085472
1538-7445
15387445
shingle_title_1 CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
shingle_title_2 CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
shingle_title_3 CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
shingle_title_4 CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
timestamp 2025-06-30T23:37:23.576Z
titel CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
titel_suche CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
topic WW-YZ
uid ipn_articles_6357354