EMAIL THIS PAGE TO A FRIEND

Oncotarget

Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia.


PMID 24903009

Abstract

Microenvironmental factors contribute to the immune dysfunction characterizing acute myeloid leukemia (AML). Indoleamine 2,3-dioxygenase 1 (IDO1) is an interferon (IFN)-γ-inducible enzyme that degrades tryptophan into kynurenine, which, in turn, inhibits effector T cells and promotes regulatory T-cell (Treg) differentiation. It is presently unknown whether childhood AML cells express IDO1 and whether IDO1 activity correlates with patient outcome. We investigated IDO1 expression and function in 37 children with newly diagnosed AML other than acute promyelocytic leukemia. Blast cells were cultured with exogenous IFN-γ for 24 hours, followed by the measurement of kynurenine production and tryptophan consumption. No constitutive expression of IDO1 protein was detected in blast cells from the 37 AML samples herein tested. Conversely, 19 out of 37 (51%) AML samples up-regulated functional IDO1 protein in response to IFN-γ. The inability to express IDO1 by the remaining 18 AML samples was not apparently due to a defective IFN-γ signaling circuitry, as suggested by the measurement of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Co-immunoprecipitation assays indicated the occurrence of physical interactions between STAT3 and IDO1 in AML blasts. In line with this finding, STAT3 inhibitors abrogated IDO1 function in AML blasts. Interestingly, levels of IFN-γ were significantly higher in the bone marrow fluid of IDO-expressing compared with IDO-nonexpressing AMLs. In mixed tumor lymphocyte cultures (MTLC), IDO-expressing AML blasts blunted the ability of allogeneic naïve T cells to produce IFN-γ and promoted Treg differentiation. From a clinical perspective, the 8-year event-free survival was significantly worse in IDO-expressing children (16.4%, SE 9.8) as compared with IDO-nonexpressing ones (48.0%, SE 12.1; p=0.035). These data indicate that IDO1 expression by leukemia blasts negatively affects the prognosis of childhood AML. Moreover, they speak in favor of the hypothesis that IDO can be targeted, in adjunct to current chemotherapy approaches, to improve the clinical outcome of children with AML.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

N7389
3-Nitro-L-tyrosine, crystalline
C9H10N2O5
61250
DL-Kynurenine, ≥95.0% (NT)
C10H12N2O3
T0254
L-Tryptophan, reagent grade, ≥98% (HPLC)
C11H12N2O2
T8941
L-Tryptophan, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, 99.0-101.0%
C11H12N2O2
T4196
L-Tryptophan, PharmaGrade, Ajinomoto, EP, JP, USP, Manufactured under appropriate GMP controls for pharma or biopharmaceutical production, suitable for cell culture
C11H12N2O2
93659
L-Tryptophan, BioUltra, ≥99.5% (NT)
C11H12N2O2
51145
L-Tryptophan, certified reference material, TraceCERT®
C11H12N2O2
T9159
Trichloroacetic acid, BioXtra, ≥99.0%
C2HCl3O2
T6399
Trichloroacetic acid, ACS reagent, ≥99.0%
C2HCl3O2
T4885
Trichloroacetic acid, ≥99.0% (titration)
C2HCl3O2
T8657
Trichloroacetic acid, for electrophoresis, suitable for fixing solution (for IEF and PAGE gels), ≥99%
C2HCl3O2
91228
Trichloroacetic acid, BioUltra, ≥99.5% (T)
C2HCl3O2
91230
Trichloroacetic acid, ACS reagent, for the determination of Fe in blood according to Heilmeyer, ≥99.5%
C2HCl3O2
27242
Trichloroacetic acid, puriss., meets analytical specification of Ph. Eur., USP 21, 99-100.5% (calc. to the dried substance)
C2HCl3O2
T0699
Trichloroacetic acid solution, 6.1 N
C2HCl3O2
47658-U
Trichloroacetic acid solution, certified reference material, 1000 μg/mL in methyl tert-butyl ether
C2HCl3O2