Abstract
Inhibition of IRAK1/4 suppresses T-ALL progression and increases sensitivity to chemotherapy.
Major finding: Inhibition of IRAK1/4 suppresses T-ALL progression and increases sensitivity to chemotherapy.
Mechanism: IRAK1/4 promotes T-ALL proliferation and survival via TRAF6-dependent stabilization of MCL1.
Impact: Targeted inhibition of IRAK1/4 signaling may prevent or overcome chemoresistance in T-ALL.
Adults with T-cell acute lymphoblastic leukemia (T-ALL) have an increased risk of early tumor recurrence following chemotherapy treatment, indicating that more effective targeted therapies are needed. Signaling via the toll-like receptor (TLR)–myeloid differentiation primary response 88 (MyD88)–IL1 receptor-associated kinase (IRAK) pathway has been implicated in T-cell activation and survival, prompting Li and colleagues to investigate the role of this pathway in T-ALL. IRAK1 and IRAK4 were overexpressed and activated in multiple T-ALL cell lines and patient-derived T-ALL samples compared with other tumors and normal T cells. IRAK activation via stimulation with TLR2 ligand increased T-ALL cell proliferation, suggesting that IRAK signaling promotes T-ALL progression. Consistent with this idea, depletion of IRAK1/4 or inhibition of IRAK1/4 activity using a selective small-molecule inhibitor decreased T-ALL cell proliferation in vitro and impaired T-ALL expansion in vivo; this effect was due to a delay in cell-cycle entry rather than induction of apoptosis. High-throughput screening of FDA-approved compounds identified vincristine and the BCL2 inhibitor ABT-737 as therapeutic agents whose cytotoxic activity was potentiated by IRAK1/4 inhibition. Indeed, combined treatment with the IRAK1/4 inhibitor and ABT-737 or vincristine synergistically reduced T-ALL burden and prolonged survival in tumor-bearing mice. Mechanistically, IRAK1/4 blockade decreased T-ALL cell survival and enhanced chemotherapy sensitivity via destabilization of the anti-apoptotic protein myeloid cell leukemia 1 (MCL1); IRAK activation stimulated the interaction of MCL1 with the E3 ubiquitin ligase TNF receptor–associated factor 6 (TRAF6) and subsequent K63-linked MCL1 polyubiquitination. Overexpression of MCL1 reversed the therapeutic benefits induced by combined IRAK1/4 inhibitor and ABT-737 treatment both in vitro and in vivo. These data reveal the role of the MyD88–IRAK pathway in T-ALL pathogenesis and suggest that IRAK1/4 inhibition may enhance the efficacy of chemotherapeutic drugs.
