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Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia.

Authors: Bogdan B. Dumitriu, Xingmin X. Feng, Danielle M DM. Townsley, Yasutaka Y. Ueda, Tetsuichi T. Yoshizato, Rodrigo T RT. Calado, Yanqin Y. Yang, Yoshiyuki Y. Wakabayashi, Sachiko S. Kajigaya, Seishi S. Ogawa, Jun J. Zhu, Neal S NS. Young
Published: 11/18/2014, Blood


The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs). Most patients respond to immunosuppressive therapies, but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (-7). Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of evolution to -7, and all had a dominant HSPC clone bearing specific acquired mutations. However, mutations in genes associated with MDS/AML were present in only 4 cases. Patients who evolved to MDS and AML showed marked progressive telomere attrition before the emergence of -7. Single telomere length analysis confirmed accumulation of short telomere fragments of individual chromosomes. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML after SAA, and provides a possible mechanism for development of aneuploidy.

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