Abstract
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.
Highlights
Treatment outcomes in patients with relapsed T-cell acute lymphoblastic leukemia (T-ALL) as well as in certain high-risk subgroups of these patients, even with frontline therapy, are dismal and associated with the persistence of leukemia-initiating cells (LICs) [1,2,3]
Bromodomaincontaining protein 4 (BRD4) regulates NOTCH1, MYC, and CD44 expression in T-ALL and CD44 is a direct transcriptional target of BRD4 Our recent studies showed that pharmacological inhibition of BRD4 affects the expression of Myc, CD44, and Notch1 target genes in acute myeloid leukemia (AML) [24]
Notch1, Myc, and CD44 are implicated to have a role in the persistence of these LICs in T-ALL cases [3, 5, 8]
Summary
BRD4 regulates NOTCH1, MYC, and CD44 expression in T-ALL and CD44 is a direct transcriptional target of BRD4 Our recent studies showed that pharmacological inhibition of BRD4 affects the expression of Myc, CD44, and Notch target genes in AML [24]. To obtain a global view of the transcriptional changes in T-ALL with the BRD4 degrader, here we performed genome-wide gene expression profiling (GEP) of SUP-T1 cells after
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