Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies
Zhaoyang Li, … , Patrick Brown, Eduardo Davila
Zhaoyang Li, … , Patrick Brown, Eduardo Davila
Published February 2, 2015
Citation Information: J Clin Invest. 2015;125(3):1081-1097. https://doi.org/10.1172/JCI75821.
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Research Article Oncology

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

Abstract

Signaling via the MyD88/IRAK pathway in T cells is indispensable for cell survival; however, it is not known whether this pathway functions in the progression of T acute lymphoblastic leukemia (T-ALL). Here, we determined that compared with thymic and peripheral T cells, T-ALL cells from patients have elevated levels of IRAK1 and IRAK4 mRNA as well as increased total and phosphorylated protein. Targeted inhibition of IRAK1 and IRAK4, either with shRNA or with a pharmacological IRAK1/4 inhibitor, dramatically impeded proliferation of T-ALL cells isolated from patients and T-ALL cells in a murine leukemia model; however, IRAK1/4 inhibition had little effect on cell death. We screened several hundred FDA-approved compounds and identified a set of drugs that had enhanced cytotoxic activity when combined with IRAK inhibition. Administration of an IRAK1/4 inhibitor or IRAK knockdown in combination with either ABT-737 or vincristine markedly reduced leukemia burden in mice and prolonged survival. IRAK1/4 signaling activated the E3 ubiquitin ligase TRAF6, increasing K63-linked ubiquitination and enhancing stability of the antiapoptotic protein MCL1; therefore, IRAK inhibition reduced MCL1 stability and sensitized T-ALL to combination therapy. These studies demonstrate that IRAK1/4 signaling promotes T-ALL progression through stabilization of MCL1 and suggest that impeding this pathway has potential as a therapeutic strategy to enhance chemotherapeutic efficacy.

Authors

Zhaoyang Li, Kenisha Younger, Ronald Gartenhaus, Ann Mary Joseph, Fang Hu, Maria R. Baer, Patrick Brown, Eduardo Davila

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Figure 6

Combination treatment with IRAK1/4 inhibitor and ABT-737 or vincristine reduces T-ALL burden and prolongs host survival.

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Combination treatment with IRAK1/4 inhibitor and ABT-737 or vincristine ...
(A, B, and C) NSG mice (n = 5/group) were injected i.v. with CCRF-CEM cells (3 × 106). On days 3, 6, and 9, mice were i.p. injected with IRAK1/4 inhibitor (5 mg/kg), ABT-737 (40 mg/kg), or vincristine (0.5 mg/kg). T-ALL cell numbers were determined on day 21 by flow cytometry using anti–human CD7. Panel A shows representative dot plots from BM T-ALL cells. (B and C) T-ALL cell numbers from BM. (A–D) Average T-ALL cell numbers from 5 mice (± SD). *P < 0.05 and **P <0.01 by Student’s t test. (D) Jurkat cells (3 × 106) stably expressing IRAK1 shRNA or control shRNA were injected i.v. into NSG mice (n = 5/group). On days 3, 6, and 9, the mice were treated with ABT-737, and T-ALL cell numbers in BM were determined by flow cytometry. (E) Representative images of spleens collected from each of the different treatment groups. (F) NSG mice (n = 5/group) were injected i.v. with CCRF-CEM cells (3 × 106) and treated with IRAK1/4 inhibitor and ABT-737 alone or together on days 3, 6, and 9. Survival and power values (log-rank test) are shown. **P < 0.01 versus DMSO; P < 0.01 for combination versus IRAK1/4 inhibitor; and P < 0.05 for combination versus ABT-737.