Abstract
Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.
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Acknowledgements
We are indebted to the family for the opportunity to perform this detailed analysis and to all who collaborated on this project. We would also like to thank G Clark at the London Research Institute for the automated DNA sequencing work and A Guerra for his help with computational modeling of the SH2B3 variant and A Tordai for providing us with valuable DNA samples. This study was funded by Cancer Research UK (CR-UK) through a Clinical Research Fellowship awarded to KT and a Bloodwise programme grant (14032 to JF). Additional funding was awarded from Children with Cancer (JF), Momentum grant of the Hungarian Academy of Sciences (grant to CB) and the NVKP_16-1-2016-0004 grant of the Hungarian National Research, Development and Innovation Office (NFKIH).
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KT, JW and CB wrote the paper. KT, JW, JF, JC and CB designed research and provided materials. KT, PK, AAS and AR-M performed research. KT, JW and CC performed data analysis. KK, GB, MZ, AM and JC provided clinical data.
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Tawana, K., Wang, J., Király, P. et al. Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree. Eur J Hum Genet 25, 1020–1024 (2017). https://doi.org/10.1038/ejhg.2017.80
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DOI: https://doi.org/10.1038/ejhg.2017.80
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