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 1

IRAK1 and IRAK4 expression levels and activation status in T-ALL.

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IRAK1 and IRAK4 expression levels and activation status in T-ALL. (A) M...
(A) Microarray (GEO GSE36133) analysis of IRAK4 and IRAK1 gene expression levels in 917 tumor cell lines, grouped as indicated. Lines, bars, and whiskers represent the median, quartiles, and minimum and maximum values, respectively. (B) Expression levels of the indicated proteins in various T-ALL lines and other neoplastic T cell lines were determined by Western blot analysis. GAPDH served as a loading control. (C) Confocal microscopic images showing IF staining of IRAK1 and IRAK4 protein in CCRF-CEM, Jurkat, and MOLT4 cells (original magnification, ×40). (D) Microarray analysis (GEO GSE46170) of IRAK1 and IRAK4 mRNA levels in sorted thymic T cells (n = 7) and patient peripheral T-ALL (n = 31) cells. Each symbol represents 1 patient, and whiskers represent the median and quartile values. P < 0.05 by Student’s t test. (E) Total or p-IRAK1 and p-IRAK4 and IRAK2 protein levels in PBMCs, as well as patient T-ALL cells, were examined by Western blotting. GAPDH served as a loading control.