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Stem cell biology

Clonal PIGA mosaicism and dynamics in paroxysmal nocturnal hemoglobinuria

Leukemia volume 32, pages 2507–2511 (2018)Cite this article

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Somatic PIGA gene mutations initiate pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) [1, 2] and exemplify evolutional somatic adaptability of hematopoietic stem cells (HSCs). The resultant glycosylphosphatidylinositol (GPI) anchor-deficient phenotype appears to offer a growth and/or survival advantage over other unaffected HSCs [3, 4] in the context of immune-mediated bone marrow failure [5] explaining the unique association of PNH with aplastic anemia (AA). Recently, additional mutations in genes other than PIGA were identified in PNH clones, offering an explanation for intrinsic expansion drive of PNH clones irrespective of or after the initial immune escape occurred [6]. Multiple PIGA mutations have been discovered at very low frequencies in healthy individuals [7], as well as in isolated reports of occasional PNH patients [8, 9] and thus observation did not lead to the appreciation that the phenomenon of an oligoclonal disease origin may be ubiquitous and potentially essential for the pathogenesis of PNH. PIGA mutant cells fail to expand in engineered animal models [10], suggesting that additional permissive conditions and factors are required for PNH clone evolution. Using next generation sequencing (NGS) of the PIGA gene and cell sorting by flow cytometry, our goal was to determine if we could improve PIGA mutant clone detection and gain insight into PNH clonal dynamics through longitudinal monitoring. According to theoretical stipulations ~20% patients may harbor >1 PIGA mutant hematopoietic stem cell (HSC) [11]. The recently described acquisition of multiple lesions at HLA loci in AA represents an analogous scenario of immune evasion and somatic adaptability of HSCs [12, 13].

We set out to experimentally challenge this hypothesis, and determine if, in addition to the classic two-hit scenario characterized by a founder PIGA mutation followed by a subclonal driver hit, there are more complex, potentially mosaic, clonal dynamics; whereby multiple PIGA clones compete for dominance. We also asked whether stratifying AA/PNH and classic PNH patients would provide additional insight as to the process of clonal selection.

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Acknowledgements

This work was supported by grants from the NIH (RO1HL-082983, U54 RR019391, and K24 HL-077522, to J.P. Maciejewski); the Aplastic Anemia & MDS International Foundation; the Robert Duggan Charitable Fund; Scott Hamilton CARES.

Author contributions

MJC analyzed data, performed research, contributed to study design, and wrote the manuscript. BP analyzed data computationally and contributed to study design. CMH performed research. YN, MWW, HM contributed to study design. TB performed clinical research. TR and JPM wrote the manuscript and contributed to study design. JPM is the principal investigator.

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Michael J. Clemente, Bartlomiej Przychodzen, Cassandra M. Hirsch, Yasunobu Nagata, Taha Bat, Tomas Radivoyevitch, Hideki Makishima & Jaroslaw P. Maciejewski

  2. Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Tomas Radivoyevitch

  3. Pediatric Hematology & Oncology, Center for Pediatrics and Adolescent Medicine, Freiburg, Germany

    Marcin W. Wlodarski

  4. Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Jaroslaw P. Maciejewski

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  1. Michael J. Clemente
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  9. Jaroslaw P. Maciejewski
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Correspondence to Michael J. Clemente.

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Clemente, M.J., Przychodzen, B., Hirsch, C.M. et al. Clonal PIGA mosaicism and dynamics in paroxysmal nocturnal hemoglobinuria. Leukemia 32, 2507–2511 (2018). https://doi.org/10.1038/s41375-018-0138-5

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