Leukemias: Molecular Pathogenesis and Influence of the Microenvironment

Dear Colleagues,

In recent years, accumulating evidence has highlighted the critical role played by the bone marrow microenvironment (BMME) in the progression of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Both are clonal hematologic malignancies arising from dysregulated hematopoietic stem and progenitor cells (HSPCs). While AML is characterized by the uncontrolled proliferation and accumulation of immature myeloid blasts, MDS is primarily a disorder of ineffective hematopoiesis, where half of patients’ conditions evolve into AML in high-risk cases. A hallmark of both MDS and AML is the persistence of leukemic stem cells (LSCs), which remain resistant to conventional chemotherapy and contribute to disease progression. It is believed that LSCs are protectived within bone marrow niches, allowing them to evade immune surveillance and resist cytotoxic therapies. The leukemic niche is composed of mesenchymal stromal cells (MSCs), osteoblasts, endothelial cells, adipocytes, megakaryocytes and immune cells. Cell–cell communication within this niche is vital for regulating leukemic cell behavior, influencing disease progression, treatment response, and potential relapse. Given the integral role of the molecular and microenvironmental dependencies in MDS and AML pathogenesis, therapeutic strategies targeting both intrinsic leukemic alterations and the protective tumor niche are greatly needed. Emerging therapies that target the disruption of the leukemic microenvironment, reactivate immune surveillance, and selectively eradicate LSCs hold promise for more effective and durable treatment approaches. However, to overcome therapy resistance and treatment failure, it is equally critical to develop innovative technologies and preclinical models that accurately recapitulate disease heterogeneity, drug resistance mechanisms, and clonal evolution. Advanced ex vivo culture systems, patient-derived xenografts (PDXs), organoid models, extracellular vesicles, and single-cell omics technologies will be essential for deciphering resistance pathways and identifying novel therapeutic vulnerabilities in MDS and AML. Only through the combined efforts of therapeutic innovation and technological advancement can we truly transform the treatment landscape for these aggressive hematologic malignancies, enabling more precise and effective clinical interventions.

Dr. Juana Serrano-López
Dr. Somchai Chutipongtanate
Guest Editors

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