Azelaic acid attenuates CCL2/CCR2 axis-mediated skin trafficking of acute myeloid leukemia cells through NF-κB/MAPK signaling modulation in keratinocytes

Background: The involvement of CCL2/CCR2 in leukemic cell infiltration into the skin, specifically in leukemia cutis (LC), remains largely unexplored. Oxidative stress has been demonstrated to induce the upregulation of CCL2 expression, while the antioxidant properties of azelaic acid (AZA) have been proven to exert anti-acute myeloid leukemia (AML) effects.

Aims: To investigate the role of CCL2/CCR2 in the pathogenesis of leukemia cutis, and to evaluate whether azelaic acid (AZA) can inhibit the infiltration of leukemic cells into the skin and its possible mechanism.

Methods: The migratory capacity of leukemic cells toward skin tissue was evaluated in vitro to determine the effects of CCL2/CCR2 and its modulation by AZA treatment. Concurrently, the regulatory effects of AZA on the NF-κB/MAPK signaling pathway in keratinocytes were investigated. In vivo studies were conducted using a patient-derived xenograft (PDX) AML mouse model, wherein AZA was administered via tail vein injection. A quantitative assessment of leukemic cell infiltration in skin tissues was performed to compare the therapeutic efficacy of AZA treatment versus untreated controls.

Results: AZA treatment significantly reduced CCL2 secretion in keratinocytes and decreased CCR2 expression in AML cells, consequently attenuating the migratory capacity of AML cells toward keratinocytes. Mechanistically, AZA downregulated the NF-κB/MAPK signaling pathway in keratinocytes. In vivo studies using the PDX-AML mouse model demonstrated that AZA administration markedly reduced leukemic cell infiltration in skin tissues compared to untreated controls.

Conclusions: CCL2/CCR2 plays an important role in the pathogenesis of LC. AZA effectively inhibits leukemic cell infiltration into the skin by downregulating CCL2 production through negative regulation of the NF-κB/MAPK signaling pathway in keratinocytes.

Azelaic acid; CCL2/CCR2; Leukemia cutis mice model; Migration; Acute myeloid leukemia.