TY - JOUR
T1 - Targeting the NOTCH1-MYC-CD44 axis in leukemia-initiating cells in T-ALL
AU - Piya, Sujan
AU - Yang, Yaling
AU - Bhattacharya, Seemana
AU - Sharma, Priyanka
AU - Ma, Huaxian
AU - Mu, Hong
AU - He, Hua
AU - Ruvolo, Vivian
AU - Baran, Natalia
AU - Davis, R. Eric
AU - Jain, Abhinav K.
AU - Konopleava, Marina
AU - Kantarjian, Hagop
AU - Andreeff, Michael
AU - You, M. James
AU - Borthakur, Gautam
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/5
Y1 - 2022/5
N2 - The NOTCH1-MYC-CD44 axis integrates cell-intrinsic and extrinsic signaling to ensure the persistence of leukemia-initiating cells (LICs) in T-cell acute lymphoblastic leukemia (T-ALL) but a common pathway to target this circuit is poorly defined. Bromodomain-containing protein 4 (BRD4) is implicated to have a role in the transcriptional regulation of oncogenes MYC and targets downstream of NOTCH1, and here we demonstrate its role in transcriptional regulation of CD44. Hence, targeting BRD4 will dismantle the NOTCH1-MYC-CD44 axis. As a proof of concept, degrading BRD4 with proteolysis targeting chimera (PROTAC) ARV-825, prolonged the survival of mice in Notch1 mutated patient-derived xenograft (PDX) and genetic models (ΔPTEN) of T-ALL. Single-cell proteomics analysis from the PDX model, demonstrated quantitative reduction of LICs (CD34+ CD7+ CD19−) and downregulation of the NOTCH1-MYC-CD44 axis, along with cell cycle, apoptosis and PI3K/Akt pathways. Moreover, secondary transplantation from PDX and ΔPTEN models of T-ALL, confirmed delayed leukemia development and extended survival of mice engrafted with T-ALL from ARV-825 treated mice, providing functional confirmation of depletion of LICs. Hence, BRD4 degradation is a promising LIC-targeting therapy for T-ALL.
AB - The NOTCH1-MYC-CD44 axis integrates cell-intrinsic and extrinsic signaling to ensure the persistence of leukemia-initiating cells (LICs) in T-cell acute lymphoblastic leukemia (T-ALL) but a common pathway to target this circuit is poorly defined. Bromodomain-containing protein 4 (BRD4) is implicated to have a role in the transcriptional regulation of oncogenes MYC and targets downstream of NOTCH1, and here we demonstrate its role in transcriptional regulation of CD44. Hence, targeting BRD4 will dismantle the NOTCH1-MYC-CD44 axis. As a proof of concept, degrading BRD4 with proteolysis targeting chimera (PROTAC) ARV-825, prolonged the survival of mice in Notch1 mutated patient-derived xenograft (PDX) and genetic models (ΔPTEN) of T-ALL. Single-cell proteomics analysis from the PDX model, demonstrated quantitative reduction of LICs (CD34+ CD7+ CD19−) and downregulation of the NOTCH1-MYC-CD44 axis, along with cell cycle, apoptosis and PI3K/Akt pathways. Moreover, secondary transplantation from PDX and ΔPTEN models of T-ALL, confirmed delayed leukemia development and extended survival of mice engrafted with T-ALL from ARV-825 treated mice, providing functional confirmation of depletion of LICs. Hence, BRD4 degradation is a promising LIC-targeting therapy for T-ALL.
UR - http://www.scopus.com/inward/record.url?scp=85124828961&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124828961&partnerID=8YFLogxK
U2 - 10.1038/s41375-022-01516-1
DO - 10.1038/s41375-022-01516-1
M3 - Article
C2 - 35173274
AN - SCOPUS:85124828961
SN - 0887-6924
VL - 36
SP - 1261
EP - 1273
JO - Leukemia
JF - Leukemia
IS - 5
ER -