Kynurenine pathway impact on immune evasion and inflammation in acute myeloid leukemia.

Source: PubMed, NCBI / U.S. National Library of Medicine

Acute myeloid leukemia (AML) involves immune dysregulation and evasion, in which tryptophan catabolism via the kynurenine pathway (KP) is central. Leukemic blasts often overexpress indoleamine 2,3-dioxygenase-1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), driving excess L-kynurenine (Kyn) production. Kyn activates the aryl hydrocarbon receptor (AhR), inducing interleukin-6 (IL-6) secretion and STAT3 phosphorylation with NF-κB co-activation, sustaining chronic inflammation. Concomitantly, KP activation is immunosuppressive: Kyn biases T cells toward FoxP3+ regulatory phenotypes, drives exhaustion of T and NK cells, and impairs dendritic and B-cell function, yielding an immunosuppressive milieu rich in IL-10 and IL-35. Together, these actions link chronic inflammation to immune tolerance in AML. By contrast, while upstream enzymes (IDO1/TDO2) are well studied, downstream KP metabolites remain poorly characterized in AML. In other systems, kynurenic acid (KYNA) mediates anti-inflammatory GPR35/AhR signaling, whereas 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) generate reactive oxygen species, activate NF-κB-dependent cytokine cascades, and induce T-cell apoptosis. Collectively, the extended KP emerges as a nexus linking inflammatory signaling and immunosuppression in AML, with implications for disease progression, immune escape, and resistance, warranting further investigation.