Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia

Publication Date:
2018-05-16
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
Published by:
http://www.aacr.org/
_version_ 1839208051035340800
autor Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
beschreibung Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3 -mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3 -mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3 -mutated AML cells and stem/progenitor cells in vitro . The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3 -mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3 -mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR .
citation_standardnr 6258920
datenlieferant ipn_articles
feed_id 9363
feed_publisher The American Association for Cancer Research (AACR)
feed_publisher_url http://www.aacr.org/
insertion_date 2018-05-16
journaleissn 1557-3265
journalissn 1078-0432
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association for Cancer Research (AACR)
quelle Clinical Cancer Research
relation http://clincancerres.aacrjournals.org/cgi/content/short/24/10/2417?rss=1
search_space articles
shingle_author_1 Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
shingle_author_2 Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
shingle_author_3 Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
shingle_author_4 Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
shingle_catch_all_1 Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3 -mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3 -mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3 -mutated AML cells and stem/progenitor cells in vitro . The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3 -mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3 -mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR .
Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_2 Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3 -mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3 -mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3 -mutated AML cells and stem/progenitor cells in vitro . The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3 -mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3 -mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR .
Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_3 Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3 -mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3 -mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3 -mutated AML cells and stem/progenitor cells in vitro . The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3 -mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3 -mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR .
Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_4 Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3 -mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3 -mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3 -mutated AML cells and stem/progenitor cells in vitro . The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3 -mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3 -mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR .
Jiang, X., Mak, P. Y., Mu, H., Tao, W., Mak, D. H., Kornblau, S., Zhang, Q., Ruvolo, P., Burks, J. K., Zhang, W., McQueen, T., Pan, R., Zhou, H., Konopleva, M., Cortes, J., Liu, Q., Andreeff, M., Carter, B. Z.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_title_1 Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
shingle_title_2 Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
shingle_title_3 Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
shingle_title_4 Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
timestamp 2025-07-31T23:44:40.606Z
titel Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
titel_suche Disruption of Wnt/{beta}-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
topic WW-YZ
uid ipn_articles_6258920