Aging-driven reprogramming of CD34⁺ hematopoietic stem cells in leukemogenesis: Mechanisms and therapeutic...

Aging is a major driver of hematological impairment and a significant risk factor for hematologic malignancies. CD34⁺ hematopoietic stem and progenitor cells (HSPCs) represent a critical cellular compartment in which age-related changes converge to promote leukemogenesis. This review synthesizes contemporary findings on the interplay between intrinsic hallmarks of aging, including genomic instability, telomere attrition, epigenetic drift, and mitochondrial dysfunction, and extrinsic factors, including chronic inflammation and bone marrow niche remodeling, in the reprogramming of CD34⁺ cell fate. These alterations promote clonal hematopoiesis of indeterminate potential (CHIP), impair immune competence, and increase susceptibility to malignant transformation. Special attention is directed towards CD34⁺CD38⁻ subsets, which possess leukemic stem cell (LSC) functionality and demonstrate resistance to standard treatments. Emerging biomarkers, including CD123, CD96, IL1RAP, and CD133, are discussed in relation to disease progression and therapeutic targeting. We emphasize how aging-related inflammatory signaling and metabolic changes preferentially benefit pre-leukemic clones. Ultimately, we investigate therapeutic approaches designed to disrupt leukemogenesis by focusing on aging mechanisms, the senescent microenvironment, and vulnerabilities specific to leukemic stem cells (LSCs). This review contextualizes CD34⁺ cell biology within aging mechanisms, offering a cohesive view on illness onset and highlighting prospects for early intervention in older populations.