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.
journal_name
Leukemiajournal_title
Leukemiaauthors
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,Verstodoi
10.1038/s41375-018-0334-3subject
Has Abstractpub_date
2019-06-01 00:00:00pages
1373-1386issue
6eissn
0887-6924issn
1476-5551pii
10.1038/s41375-018-0334-3journal_volume
33pub_type
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