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Polyclonal evolution of Fanconi anemia to MDS and AML revealed at single cell resolution
Lixian Chang1, Zejia Cui2, Deyang Shi1
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China.
Background:
Fanconi anemia (FA) is a rare disease of bone marrow failure. FA patients are prone to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, the molecular clonal evolution of the progression from FA to MDS/AML remains elusive.
Methods:
Herein, we performed a comprehensive genomic analysis using an FA patient (P1001) sample that transformed to MDS and subsequently AML, together with other three FA patient samples at the MDS stage.
Results:
Our finding showed the existence of polyclonal pattern in these cases at MDS stage. The clonal evolution analysis of FA case (P1001) showed the mutations of UBASH3A, SF3B1, RUNX1 and ASXL1 gradually appeared at the later stage of MDS, while the IDH2 alteration become the dominant clone at the leukemia stage. Moreover, single-cell sequencing analyses further demonstrated a polyclonal pattern was present at either MDS or AML stages, whereas IDH2 mutated cell clones appeared only at the leukemia stage.
Conclusions:
We thus propose a clonal evolution model from FA to MDS and AML for this patient. The results of our study on the clonal evolution and mutated genes of the progression of FA to AML are conducive to understanding the progression of the disease that still perplexes us.
Insights
Fanconi anemia (FA) progression to MDS and AML involves a polyclonal pattern. Specific mutations like IDH2 emerge later, driving leukemia development in FA patients.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Fanconi anemia (FA) is a rare bone marrow failure disorder.
- FA patients have an increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
- The molecular mechanisms driving FA to MDS/AML transformation are not fully understood.
Purpose of the Study:
- To investigate the clonal evolution of Fanconi anemia (FA) to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
- To identify key genetic mutations associated with disease progression in FA.
Main Methods:
- Comprehensive genomic analysis of FA patient samples at MDS and AML stages.
- Single-cell sequencing to analyze clonal heterogeneity.
Main Results:
- A polyclonal mutational pattern was observed in FA patients with MDS and AML.
- Mutations in UBASH3A, SF3B1, RUNX1, and ASXL1 appeared during MDS progression.
- IDH2 alterations emerged as dominant clones during the transition to AML.
Conclusions:
- A proposed clonal evolution model for FA progression to MDS and AML.
- Identified key mutated genes and clonal dynamics in FA-associated leukemogenesis.
- Findings contribute to understanding the complex progression of FA to AML.
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