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Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree
Kiran Tawana1, Jun Wang2, Péter A Király3
1Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
European Journal of Human Genetics : EJHG
|May 18, 2017
Summary
Three sisters with a RUNX1 gene variant developed acute myeloid leukemia (AML) due to independent JAK-STAT pathway mutations. This convergent evolution highlights a high-risk AML subtype.
Area of Science:
- Genetics
- Hematology
- Oncology
Background:
- Germline variants in the RUNX1 gene are linked to familial platelet disorders and acute leukemia.
- Somatic events driving leukemic transformation in these families are diverse and poorly understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying acute myeloid leukemia (AML) development in a family with a germline RUNX1 nonsense variant.
- To define the patterns of leukemia initiation across family members.
Main Methods:
- Whole-exome sequencing of tumor samples from three affected siblings.
- Chromosomal characterization of tumor cells.
- Analysis of germline and somatic variants, including copy number alterations and uniparental disomy.
Main Results:
- All three siblings developed acute myelomonocytic leukemia (AML) at age 5, each harboring the germline RUNX1 variant c.601C>T (p.(Arg201*)).
- Tumor sequencing revealed independent acquisition of variants in the JAK-STAT pathway (JAK2, SH2B3) in all siblings.
- Chromosomal analysis showed copy number gains and uniparental disomy affecting RUNX1, JAK2, and SH2B3, indicating pathway cooperation.
- One sibling with myelodysplasia lacked JAK2/SH2B3 variants, suggesting their specific role in leukemic transformation.
Conclusions:
- This study presents the first example of convergent AML evolution in a RUNX1 pedigree.
- Recurrent acquisition of JAK-STAT pathway variants drives high-risk AML with chemotherapy resistance and relapse.
- Cooperation between RUNX1 and JAK-STAT pathway disruptions is critical for leukemogenesis in this context.
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