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

Research output: Contribution to journal › Article › peer-review

33 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
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 - 1 Jun 2019
Externally published	Yes

Access to Document

10.1038/s41375-018-0334-3

Cite this

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

@article{c73cfa490a6941008aa1ec9c8b50fe73,

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 = "Publisher Copyright: {\textcopyright} 2018, Springer Nature Limited.",

year = "2019",

month = jun,

day = "1",

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

language = "English",

volume = "33",

pages = "1373--1386",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Springer Nature",

number = "6",

}

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

TY - JOUR

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85058935952&partnerID=8YFLogxK

U2 - 10.1038/s41375-018-0334-3

DO - 10.1038/s41375-018-0334-3

M3 - Article

C2 - 30575820

AN - SCOPUS:85058935952

SN - 0887-6924

VL - 33

SP - 1373

EP - 1386

JO - Leukemia

JF - Leukemia

IS - 6

ER -

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

Abstract

Access to Document

Fingerprint

Cite this