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Myeloid lineage-selective growth of revertant cells in Fanconi anaemia
Satoshi Hamanoue1, Hiroshi Yagasaki, Toshihisa Tsuruta
1Division of Genetic Diagnosis, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Abstract:
Fanconi anaemia (FA) is a genetically heterogeneous chromosome instability syndrome characterised by bone marrow failure and congenital anomalies. Although an increasing number of reports suggest that reversion mosaicism noted in peripheral blood lymphocytes (PBLs) is associated with mild haematopoietic failure in FA, myeloid cells are rarely directly examined. We here report a patient with prolonged mild pancytopenia in whom proliferation of revertant cells was detected in mature myeloid cells but not in PBLs. While this patient had inherited heterozygous mutations, 2546delC and 3720-3724del, in the major FA gene FANCA, Epstein-Barr virus-immortalised lymphoblastoid cells from the patient had 2546C > T instead of 2546delC, resulting in expression of a functional missense protein. As the identical reversion was detected in polymorphonuclear granulocytes and mononuclear phagocytes, sustained haematopoiesis in the patient can be attributed to a selective growth advantage of revertant myeloid cells. It is noteworthy that such a myeloid lineage-selective mosaicism is overlooked in routine examination of PBLs. Recognition of this status will expand the role of reversion mosaicism in the pathophysiology of FA.
Insights
Fanconi anaemia (FA) reversion mosaicism in myeloid cells, not lymphocytes, explains mild pancytopenia. This myeloid-specific advantage of revertant cells is crucial for sustained hematopoiesis in FA patients.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Fanconi anaemia (FA) is a genetic disorder causing bone marrow failure and congenital issues.
- Reversion mosaicism in lymphocytes is linked to milder FA, but myeloid cells are seldom studied.
- Myeloid lineage-specific reversion mosaicism in FA remains poorly understood.
Purpose of the Study:
- To investigate the role of reversion mosaicism in myeloid cells in a patient with prolonged mild pancytopenia.
- To determine if myeloid cell reversion explains sustained hematopoiesis in FA.
- To highlight the diagnostic significance of myeloid lineage-selective mosaicism in FA.
Main Methods:
- Analysis of a patient with mild pancytopenia and suspected FA.
- Examination of reversion mosaicism in peripheral blood lymphocytes (PBLs) and mature myeloid cells.
- Genetic sequencing of FA gene FANCA and analysis of revertant cell expression in Epstein-Barr virus-immortalised lymphoblastoid cells.
Main Results:
- Revertant cells were detected in mature myeloid cells (granulocytes, phagocytes) but not in PBLs.
- The patient inherited heterozygous FANCA mutations (2546delC, 3720-3724del).
- A functional missense FANCA protein was expressed due to a 2546C > T reversion in myeloid cells, conferring a selective growth advantage.
Conclusions:
- Myeloid lineage-selective reversion mosaicism can cause sustained hematopoiesis in FA patients.
- Routine examination of PBLs may miss crucial myeloid-specific reversion events.
- Recognizing myeloid reversion mosaicism is vital for understanding FA pathophysiology and patient management.
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