Genetic and Immunologic Interactions Driving STAT3 Signaling and Macrophage Polarization in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an increasingly recognized malignancy sustained by a dysregulated inflammatory niche, in which genetic alterations and microenvironmental signaling converge to drive pathogenesis. This review synthesizes emerging evidence linking genetic mutations and immune dysregulation in AML, proposing an integrated mutation-macrophage-signal transducer and activator of transcription 3 (STAT3) axis as a conceptual framework of disease progression. It proposes that mutations in CCAAT/enhancer-binding protein alpha (CEBPA) and Runt-related transcription factor 1 (RUNX1), despite conferring divergent genetic risk, converge on a common pathway of inflammatory cytokine overproduction, including interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10), as well as C-C motif chemokine ligand 2 (CCL2)-mediated recruitment of tumor-associated macrophages. These educated macrophages are proposed to undergo M2-like polarization, releasing oncostatin M (OSM) and IL-6, which are positioned to activate the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) survival pathway in leukemic blasts. Concurrently, IL-10 produced by regulatory T cells, stromal cells, and M2-like polarized macrophages within the leukemic niche signals through its cognate receptor to potently activate STAT3, suppressing antigen-presenting cell function, downregulating major histocompatibility complex class II (MHC class II) expression, and impairing effective anti-tumor T-cell immunity, thereby potentially reinforcing the immunosuppressive architecture that shields leukemic blasts from immune surveillance. This proposed feed-forward loop is associated with transcriptional upregulation of the anti-apoptotic factor BCL2-like 1 (BCL2L1) and the negative-feedback regulator suppressor of cytokine signaling 3 (SOCS3), a pattern consistent with chemoresistance and impaired negative-feedback control of STAT3 signaling. Translational biomarkers, including OSM, IL-6, IL-10, and SOCS3/BCL2L1 transcripts, may quantify this axis, offering a dynamic, functional complement to static genetic risk stratification. Ultimately, this proposed triad suggests that aberrant inflammation may represent a shared therapeutic vulnerability; targeting the IL-6/oncostatin M receptor (OSMR)/STAT3 signaling nodes or reprogramming macrophage polarization could, if validated, disrupt this circuit in selected mutational subtypes.