Dataset Information

Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization

ABSTRACT: IRAK4 is a therapeutic target in myeloid malignancies, but current IRAK4 inhibitors show only modest clinical efficacy in acute myeloid leukemia (1), highlighting the need for combination strategies. To identify drugs with synergistic potential alongside IRAK4 inhibitors, we conducted a high-throughput screen of 2,803 investigational and approved drugs in isogenic IRAK4-deficient and wild-type human AML cells. The top hit from this screen was the Cereblon E3 ligase modulator (CELMoD) CC-885. Validation in vitro and in vivo confirmed that CC-885 and related CELMoDs synergize with IRAK4 inhibitors to suppress leukemic cells. Among CC-885 substrates, GSPT1 loss showed the most pronounced effects in IRAK4-inhibited leukemic cells. Transcriptional and proteomic analyses revealed that CC-885 treatment led to c-Myc suppression in IRAK4-deficient leukemic cells. GSPT1 loss reduces translation efficiency, particularly for proteins with short half-lives, such as c-Myc. Accelerated c-Myc protein loss was confirmed following GSPT1 degradation in leukemic cells, with decreased protein stability observed following inhibition of IRAK4. These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298391 | GEO | 2025/09/03

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), toÂ cells treated with ND-2158 for the indicated times (Cy5).

Dataset Information

Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets