Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

Dyana T. Saenz; Warren Fiskus; Taghi Manshouri; Christopher P. Mill; Yimin Qian; Kanak Raina; Kimal Rajapakshe; Cristian Coarfa; Raffaella Soldi; Prithviraj Bose; Gautam Borthakur; Tapan M. Kadia; Joseph D. Khoury; Lucia Masarova; Agnieszka J. Nowak; Baohua Sun; David N. Saenz; Steven M. Kornblau; Steve Horrigan; Sunil Sharma; Peng Qiu; Craig M. Crews; Srdan Verstovsek; Kapil N. Bhalla

doi:10.1038/s41375-018-0334-3

Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

Dyana T. Saenz, Warren Fiskus, Taghi Manshouri, Christopher P. Mill, Yimin Qian, Kanak Raina, Kimal Rajapakshe, Cristian Coarfa, Raffaella Soldi, Prithviraj Bose, Gautam Borthakur, Tapan M. Kadia, Joseph D. Khoury, Lucia Masarova, Agnieszka J. Nowak, Baohua Sun, David N. Saenz, Steven M. Kornblau, Steve Horrigan, Sunil SharmaPeng Qiu, Craig M. Crews, Srdan Verstovsek, Kapil N. Bhalla

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29 Scopus citations

Abstract

Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear β-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of β-catenin or treatment with BC2059 that disrupts binding of β-catenin to TBL1X (TBL1) depleted nuclear β-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2, and Survivin. Co-targeting of β-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of the combination of β-catenin and BETP antagonists against post-MPN sAML BPCs.

Original language	English (US)
Pages (from-to)	1373-1386
Number of pages	14
Journal	Leukemia
Volume	33
Issue number	6
DOIs	https://doi.org/10.1038/s41375-018-0334-3
State	Published - Jun 1 2019

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Flow Cytometry and Cellular Imaging Facility
Cytogenetics and Cell Authentication Core

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10.1038/s41375-018-0334-3

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Saenz, D. T., Fiskus, W., Manshouri, T., Mill, C. P., Qian, Y., Raina, K., Rajapakshe, K., Coarfa, C., Soldi, R., Bose, P., Borthakur, G., Kadia, T. M., Khoury, J. D., Masarova, L., Nowak, A. J., Sun, B., Saenz, D. N., Kornblau, S. M., Horrigan, S., ... Bhalla, K. N. (2019). Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML. Leukemia, 33(6), 1373-1386. https://doi.org/10.1038/s41375-018-0334-3

Saenz, DT, Fiskus, W, Manshouri, T, Mill, CP, Qian, Y, Raina, K, Rajapakshe, K, Coarfa, C, Soldi, R, Bose, P , Borthakur, G , Kadia, TM, Khoury, JD, Masarova, L, Nowak, AJ, Sun, B, Saenz, DN, Kornblau, SM, Horrigan, S, Sharma, S, Qiu, P, Crews, CM, Verstovsek, S & Bhalla, KN 2019, 'Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML', Leukemia, vol. 33, no. 6, pp. 1373-1386. https://doi.org/10.1038/s41375-018-0334-3

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title = "Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML",

abstract = "Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear β-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of β-catenin or treatment with BC2059 that disrupts binding of β-catenin to TBL1X (TBL1) depleted nuclear β-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2, and Survivin. Co-targeting of β-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of the combination of β-catenin and BETP antagonists against post-MPN sAML BPCs.",

author = "Saenz, {Dyana T.} and Warren Fiskus and Taghi Manshouri and Mill, {Christopher P.} and Yimin Qian and Kanak Raina and Kimal Rajapakshe and Cristian Coarfa and Raffaella Soldi and Prithviraj Bose and Gautam Borthakur and Kadia, {Tapan M.} and Khoury, {Joseph D.} and Lucia Masarova and Nowak, {Agnieszka J.} and Baohua Sun and Saenz, {David N.} and Kornblau, {Steven M.} and Steve Horrigan and Sunil Sharma and Peng Qiu and Crews, {Craig M.} and Srdan Verstovsek and Bhalla, {Kapil N.}",

note = "Funding Information: Acknowledgements The authors would like to thank the Sequencing and Microarray Core Facility and Flow Cytometry and Cellular Imaging (FCCI) Core Facility which are supported by the MD Anderson Cancer Center Support Grant 5P30 CA016672-40. This project was partially supported by CPRIT RP170295 (CC), the shared Proteomics and Metabolomics core at Baylor College of Medicine with funding from the NIH (P30 CA125123), CPRIT Proteomics and Metabolomics Core Facility RP170005 (K Rajapakshe and CC), and the NCI-recognized Dan L. Duncan Cancer Center. CMC acknowledges support from the National Institutes of Health (Grant number R35 CA197589). KNB acknowledges support from the National Institutes of Health (Grant number R01 CA173877). This research is supported in part by the MD Anderson Cancer Center Leukemia SPORE (P50 CA100632). Publisher Copyright: {\textcopyright} 2018, Springer Nature Limited.",

year = "2019",

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doi = "10.1038/s41375-018-0334-3",

language = "English (US)",

volume = "33",

pages = "1373--1386",

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T1 - Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

AU - Saenz, Dyana T.

AU - Fiskus, Warren

AU - Manshouri, Taghi

AU - Mill, Christopher P.

AU - Qian, Yimin

AU - Raina, Kanak

AU - Rajapakshe, Kimal

AU - Coarfa, Cristian

AU - Soldi, Raffaella

AU - Bose, Prithviraj

AU - Borthakur, Gautam

AU - Kadia, Tapan M.

AU - Khoury, Joseph D.

AU - Masarova, Lucia

AU - Nowak, Agnieszka J.

AU - Sun, Baohua

AU - Saenz, David N.

AU - Kornblau, Steven M.

AU - Horrigan, Steve

AU - Sharma, Sunil

AU - Qiu, Peng

AU - Crews, Craig M.

AU - Verstovsek, Srdan

AU - Bhalla, Kapil N.

N1 - Funding Information: Acknowledgements The authors would like to thank the Sequencing and Microarray Core Facility and Flow Cytometry and Cellular Imaging (FCCI) Core Facility which are supported by the MD Anderson Cancer Center Support Grant 5P30 CA016672-40. This project was partially supported by CPRIT RP170295 (CC), the shared Proteomics and Metabolomics core at Baylor College of Medicine with funding from the NIH (P30 CA125123), CPRIT Proteomics and Metabolomics Core Facility RP170005 (K Rajapakshe and CC), and the NCI-recognized Dan L. Duncan Cancer Center. CMC acknowledges support from the National Institutes of Health (Grant number R35 CA197589). KNB acknowledges support from the National Institutes of Health (Grant number R01 CA173877). This research is supported in part by the MD Anderson Cancer Center Leukemia SPORE (P50 CA100632). Publisher Copyright: © 2018, Springer Nature Limited.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear β-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of β-catenin or treatment with BC2059 that disrupts binding of β-catenin to TBL1X (TBL1) depleted nuclear β-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2, and Survivin. Co-targeting of β-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of the combination of β-catenin and BETP antagonists against post-MPN sAML BPCs.

AB - Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear β-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of β-catenin or treatment with BC2059 that disrupts binding of β-catenin to TBL1X (TBL1) depleted nuclear β-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2, and Survivin. Co-targeting of β-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of the combination of β-catenin and BETP antagonists against post-MPN sAML BPCs.

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Targeting nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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