TY - JOUR
T1 - Mechanistic basis and efficacy of targeting the b-catenin-TCF7L2-JMJD6-c-Myc axis to overcome resistance to BET inhibitors
AU - Saenz, Dyana T.
AU - Fiskus, Warren
AU - Mill, Christopher P.
AU - Perera, Dimuthu
AU - Manshouri, Taghi
AU - Lara, Bernardo H.
AU - Karkhanis, Vrajesh
AU - Sharma, Sunil
AU - Horrigan, Stephen K.
AU - Bose, Prithviraj
AU - Kadia, Tapan M.
AU - Masarova, Lucia
AU - DiNardo, Courtney D.
AU - Borthakur, Gautam
AU - Khoury, Joseph D.
AU - Takahashi, Koichi
AU - Bhaskara, Srividya
AU - Lin, Charles Y.
AU - Green, Michael R.
AU - Coarfa, Cristian
AU - Crews, Craig M.
AU - Verstovsek, Srdan
AU - Bhalla, Kapil N.
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/4/9
Y1 - 2020/4/9
N2 - The promising activity of BET protein inhibitors (BETi's) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/ resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/ enhancers, which was associated with increased levels of nuclear b-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the b-catenin-TCF7L2-JMJD6-c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD341 sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear b-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the b-catenin-TCF7L2-JMJD6-c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.
AB - The promising activity of BET protein inhibitors (BETi's) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/ resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/ enhancers, which was associated with increased levels of nuclear b-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the b-catenin-TCF7L2-JMJD6-c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD341 sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear b-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the b-catenin-TCF7L2-JMJD6-c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.
UR - http://www.scopus.com/inward/record.url?scp=85085961763&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085961763&partnerID=8YFLogxK
U2 - 10.1182/BLOOD.2019002922
DO - 10.1182/BLOOD.2019002922
M3 - Article
C2 - 32068780
AN - SCOPUS:85085961763
SN - 0006-4971
VL - 135
SP - 1255
EP - 1269
JO - Blood
JF - Blood
IS - 15
ER -