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

Leukemia 2019 06 21;33(6):1373-1386. Epub 2018 Dec 21.

The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.

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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http://www.nature.com/articles/s41375-018-0334-3
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http://dx.doi.org/10.1038/s41375-018-0334-3DOI Listing
June 2019
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References

(Supplied by CrossRef)

W Vainchenker et al.
Blood 2017

R Rampal et al.
Blood 2014

M Kleppe et al.
Cancer Discov 2015

R Rampal et al.
Curr Opin Hematol 2014

R Rampal et al.
Proc Natl Acad Sci USA 2014

SJ Zhang et al.
Blood 2012

JY Spiegel et al.
Blood Adv 2017

E Leroy et al.
Leukemia 2017

AM Vannucchi et al.
Haematologica 2015

P Bose et al.
Blood 2017

MN Kundranda et al.
Curr Hematol Malig Rep 2012

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