Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree

Kiran Tawana, Jun Wang, Péter A. Király, Krisztián Kállay, Gábor Benyó, Marianna Zombori, Judit Csomor, Ahad Al Seraihi, Ana Rio-Machin, A. Matolcsy, Claude Chelala, Jamie Cavenagh, Jude Fitzgibbon, Csaba Bödör

Research output: Contribution to journalArticle

3 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1020-1024
Number of pages5
JournalEuropean Journal of Human Genetics
Issue number8
Publication statusPublished - Aug 1 2017


ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Tawana, K., Wang, J., Király, P. A., Kállay, K., Benyó, G., Zombori, M., Csomor, J., Al Seraihi, A., Rio-Machin, A., Matolcsy, A., Chelala, C., Cavenagh, J., Fitzgibbon, J., & Bödör, C. (2017). Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree. European Journal of Human Genetics, 25(8), 1020-1024.