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The mutational landscape of paroxysmal nocturnal hemoglobinuria revealed: new insights into clonal dominance
Stanley Chun-Wei Lee, Omar Abdel-Wahab
Stanley Chun-Wei Lee, Omar Abdel-Wahab
Published September 17, 2014
Citation Information: J Clin Invest. 2014;124(10):4227-4230. https://doi.org/10.1172/JCI77984.
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Commentary

The mutational landscape of paroxysmal nocturnal hemoglobinuria revealed: new insights into clonal dominance

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Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder of hematopoietic stem cells that has largely been considered a monogenic disorder due to acquisition of mutations in the gene encoding PIGA, which is required for glycosylphosphatidylinositol (GPI) anchor biosynthesis. In this issue of the JCI, Shen et al. discovered that PNH is in fact a complex genetic disorder orchestrated by many genetic alterations in addition to PIGA mutations. Some of these mutations predate the acquisition of PIGA mutations, while others occur later. Surprisingly, this work indicates that PNH has a clonal evolution and architecture strikingly similar to that of other myeloid neoplasms, highlighting a potentially broader mechanism of disease pathogenesis in this disorder.

Authors

Stanley Chun-Wei Lee, Omar Abdel-Wahab

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Figure 1

Clonal architecture and evolution of PNH.

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Clonal architecture and evolution of PNH.
PNH arises from an initial mut...
PNH arises from an initial mutation in PIGA (orange) or in a different founder gene (green) in HSCs. Over time, the acquisition of additional cooperating lesions, which can include additional mutations in PIGA (yellow) or other genes (blue) (e.g., TET2, SUZ12, JAK2, and U2AF1), in addition to the founder mutation, adds complexity to the clonal architecture and confers a growth advantage and subsequent progression into overt PNH. On rare occasions, PNH clones can transform into myeloid malignancies such as MDS and acute AML, or into AA. Future work to identify the complement of events responsible for the transformation of PNH into MDS or AML will be enlightening. Moreover, it will be important to determine whether AA harbors a genetic complexity and clonal architecture similar to that of PNH.
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