Mosaicism in Fanconi anemia : concise review and evaluation of published cases with focus on clinical course of blood count normalization
Nicoletti, Eileen (Rocket Pharmaceuticals, Inc., New York)
Rao, Gayatri (Rocket Pharmaceuticals, Inc., New York, NY USA)
Bueren, Juan (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Río, Paula (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Navarro Ordóñez, Susana (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Surrallés i Calonge, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Choi, Grace (Rocket Pharmaceuticals, Inc., New York)
Schwartz, Jonathan D. (Rocket Pharmaceuticals, Inc., New York)
Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia

Date:	2020
Abstract:	Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1-6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs. The online version of this article (10. 1007/s00277-020-03954-2) contains supplementary material, which is available to authorized users.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article de revisió ; Article ; Versió publicada
Subject:	Fanconi anemia ; Bone marrow failure ; Autologous stem cell transplantation ; Gene therapy ; Mosaicism
Published in:	Annals of Hematology, Vol. 99 (february 2020) , p. 913-924, ISSN 1432-0584

DOI: 10.1007/s00277-020-03954-2
PMID: 32065290

12 p, 548.1 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Published articles