In this episode of MD Newsline, Dr. Theodoros Karantanos, Assistant Professor of Medical Oncology at the Johns Hopkins University Sidney Kimmel Cancer Center, discusses the emerging role of inflammatory signaling in high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

Dr. Karantanos shares insights from his laboratory research exploring how inflammatory pathways—particularly interferon gamma and JAK-STAT signaling—contribute to treatment resistance, including resistance to venetoclax. He also highlights the impact of TP53 mutations, bone marrow microenvironment dynamics, and post-translational modifications in shaping disease progression and therapeutic response.

Inflammatory Signaling and Venetoclax Resistance
High-risk MDS and AML frequently demonstrate upregulation of inflammatory pathways. Dr. Karantanos explains how interferon gamma signaling activates the JAK-STAT cascade (JAK1/2, STAT1/3/5), leading to transcriptional programs associated with resistance to venetoclax and chemotherapy.

The Role of TP53 in Driving Inflammation
Loss of TP53 function not only impairs apoptosis but may intrinsically upregulate interferon gamma signaling within leukemic cells. This cell-intrinsic inflammatory activation may partially explain why TP53-mutated MDS and AML remain particularly difficult to treat.

Post-Translational Modifications as Resistance Drivers
Phosphorylation and ubiquitination play central roles in regulating inflammatory cascades. Dr. Karantanos emphasizes that proteomic and phospho-signature analyses are essential, as RNA expression alone cannot fully capture pathway activation under therapeutic pressure.

Bone Marrow Microenvironment and Cytokine Crosstalk
The bone marrow niche—including fibroblasts, adipocytes, endothelial cells, and immune subsets—contributes to resistance through cytokine secretion (e.g., IL-1β, TNF-α) and drug metabolism. These interactions reshape therapeutic exposure and promote survival of malignant clones.

Monocytic Leukemias and Inflammatory Activation
Monocytic AML subtypes (M4/M5) appear particularly enriched in inflammatory signaling, including interferon gamma and TNF-α activation. These subsets may represent high-priority targets for inflammation-modulating strategies.

Targeting Inflammatory Pathways: Translational Strategies
Potential therapeutic approaches include IRAK1/IRAK4 inhibitors, JAK pathway modulation, and antibody-drug conjugates targeting downstream interferon-regulated surface proteins such as CCRL2 and ICAM-1. Combination and triplet regimens may offer future improvements over venetoclax-based standards.

Single-Cell and Spatial Transcriptomics
Dr. Karantanos highlights the importance of computational biology, single-cell RNA sequencing, and spatial transcriptomics in deciphering the complex inflammatory networks within the bone marrow microenvironment. These technologies are critical for identifying actionable nodes and refining patient stratification.

Inflammatory signaling is not merely a bystander in myeloid neoplasms—it is a central driver of disease evolution and therapeutic resistance. Integrating inflammatory biomarkers, post-translational pathway profiling, and microenvironmental analysis may unlock new precision strategies for high-risk MDS and AML, particularly in TP53-mutated and monocytic subtypes where unmet need remains greatest.

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