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تسجيل

Myelodysplastic Syndromes Cell of Origin

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P980

2026-10-15

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One of the central challenges in understanding the pathogenesis of MDS has been isolating the cell of origin and understanding that cell’s mechanisms of self-renewal and propagation, both of which are necessary for the establishment of a malignant clone. The capacity for self-renewal on its face implies that the origin cell is either a hematopoietic stem cell, and thus possesses intrinsic self-renewal capabilities, or is a more differentiated myeloid progenitor that acquired the ability to self-renew. Additional alterations may confer other characteristics associated with MDS, such as enhanced proliferation, resistance to apoptosis, specific types of morphologic dysplasia, or ineffective hematopoiesis and cytopenias, at which point MDS also becomes clinically evident.

The clonal nature of MDS was first established in the 1980s by studies that showed skewed inactivation of glucose-6-phosphate dehydrogenase (G6PD), an X-linked gene, in the hematopoietic cells of female MDS patients heterozygous for G6PD deficiency. More recent studies have used deep sequencing techniques to track the clonal evolution from MDS into AML and have confirmed that in these cases, the pre-existing MDS is as highly clonal as the resulting secondary AML.

Whether MDS is a disorder of stem or early progenitor cells has been more difficult to prove. Xenotransplant experiments using immunophenotypically defined HSPCs (classically CD34+ CD38− Lin−) from MDS patients have not shown a striking proliferative or self-renewal advantage for the MDS cells compared to normal controls, and the degree to which these experiments accurately depict the clonal dynamics of MDS in humans is unclear. More recent studies combining immunophenotypic analysis with deep sequencing of clonal mutations in MDS cells have shown that the mutations appear to originate exclusively in the most primitive, stem-cell-like compartment, and others have shown that differential expansion of specific progenitor compartments may vary between different phenotypes and risk profiles of MDS. These studies have led to the conclusion that MDS is, in fact, a disorder of transformed HSCs. The conceptualization of MDS as a stem cell disorder partly explains why it is so refractory to most attempts at conventional therapy.