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 4

In vivo intervention with IRAK1/4 inhibitor reduces T-ALL numbers and delays T-ALL progression.

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In vivo intervention with IRAK1/4 inhibitor reduces T-ALL numbers and de...
(A) CCRF-CEM cells were injected i.v. into NSG mice, followed by i.p. injection with IRAK1/4 inhibitor (10 mg/kg) or DMSO on days 3, 6, and 9. Numbers of T-ALL cells (distinguished by CD7 expression) in BM and blood were determined by flow cytometry on day 21. Representative flow cytometric dot plots and average number of cells from 5 mice (± SD) are shown. (B) Jurkat cell lines with reduced IRAK1 expression were generated using lentiviral vectors and injected i.v. into NSG mice. On day 21, the number of T-ALL cells in BM and blood were measured by flow cytometry. (C) NSG mice were injected i.v. with T-ALL cells from 3 different patients. Mice with equal numbers of T-ALL cells in the blood were identified by flow cytometry on day 7 (dot plot) and injected i.p. with IRAK1/4 inhibitor or DMSO on days 7, 10, and 13. Numbers represent the percentages of T-ALL cells. T-ALL cells were enumerated in blood and BM on day 21 and are shown per 100,000 beads in the bar graphs. (D) NSG mice were injected with CCRF-CEM cells and treated with IRAK1/4 inhibitor or DMSO on days 3, 6, and 9. (A, B and D) Data are representative of 2 independent experiments (5 mice/group) and were analyzed by Student’s t test (A and B), ANOVA (C), and log-rank test (D).