TY - JOUR
T1 - Disruption of wnt/b-catenin exerts antileukemia activity and synergizes with flt3 inhibition in flt3-mutant acute myeloid leukemia
AU - Jiang, Xuejie
AU - Mak, Po Yee
AU - Mu, Hong
AU - Tao, Wenjing
AU - Mak, Duncan H.
AU - Kornblau, Steven
AU - Zhang, Qi
AU - Ruvolo, Peter
AU - Burks, Jared K.
AU - Zhang, Weiguo
AU - McQueen, Teresa
AU - Pan, Rongqing
AU - Zhou, Hongsheng
AU - Konopleva, Marina
AU - Cortes, Jorge
AU - Liu, Qifa
AU - Andreeff, Michael
AU - Carter, Bing Z.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/5/15
Y1 - 2018/5/15
N2 - Purpose: Wnt/b-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases b-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/b-catenin and FLT3 inhibition in FLT3-mutant AML. Experimental Design: Wnt/b-catenin signaling was inhibited by the b-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 b-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/b-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/b-catenin and FLT3 cooperatively decreased nuclear b-catenin and the levels of c-Myc and other Wnt/b-catenin and FLT3 signaling proteins. Importantly, b-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/b-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.
AB - Purpose: Wnt/b-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases b-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/b-catenin and FLT3 inhibition in FLT3-mutant AML. Experimental Design: Wnt/b-catenin signaling was inhibited by the b-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 b-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/b-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/b-catenin and FLT3 cooperatively decreased nuclear b-catenin and the levels of c-Myc and other Wnt/b-catenin and FLT3 signaling proteins. Importantly, b-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/b-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.
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U2 - 10.1158/1078-0432.CCR-17-1556
DO - 10.1158/1078-0432.CCR-17-1556
M3 - Article
C2 - 29463558
AN - SCOPUS:85045546270
SN - 1078-0432
VL - 24
SP - 2417
EP - 2429
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -