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. Coll...Continue Reading
References
Oct 3, 1999·Nature Genetics·W J SongD G Gilliland
Jul 11, 2006·Journal of Molecular Biology·Junjie Hu, Stevan R Hubbard
Nov 11, 2006·Leukemia·S SchnittgerT Haferlach
Mar 17, 2009·Nature Genetics·Amy V JonesNicholas C P Cross
Mar 17, 2009·Nature Genetics·Outi KilpivaaraRoss L Levine
Mar 17, 2009·Nature Genetics·Damla OlcayduRobert Kralovics
Apr 10, 2009·Blood·Claude PreudhommeHagay Sobol
Dec 17, 2009·Blood·Philip A BeerAnthony R Green
May 23, 2012·Cell·Serena Nik-ZainalUNKNOWN Breast Cancer Working Group of the International Cancer Genome Consortium
May 3, 2013·The New England Journal of Medicine·UNKNOWN Cancer Genome Atlas Research NetworkGreg Eley
Jan 10, 2014·Leukemia·M-T KrauthS Schnittger
Apr 30, 2014·Nature Genetics·Paul L AuerGuillaume Lettre
Aug 28, 2014·Nature Communications·Akihide YoshimiMineo Kurokawa
Sep 26, 2014·Leukemia·E K EngleS T Oh
Sep 1, 2015·Leukemia·I Antony-DebréC Preudhomme
Oct 24, 2015·Blood·Jane E ChurpekTimothy A Graubert
Nov 4, 2015·British Journal of Haematology·Karl HaslamElisabeth Vandenberghe
Feb 6, 2016·Blood Cancer Journal·M SakuraiH Nakajima
Nov 3, 2016·Leukemia·V I GaidzikH Döhner
Citations
Sep 30, 2020·Pediatric Hematology and Oncology·Shruti BaglaYaddanapudi Ravindranath
May 28, 2019·British Journal of Haematology·Bruno K L DuarteMargareth C Ozelo
Mar 26, 2020·Blood Advances·Anna L BrownHamish S Scott
Jan 16, 2020·Cancer Cell International·Zhao-Ming ZhongChuan-Zheng Sun
Jul 25, 2021·International Journal of Molecular Sciences·Klaus FortscheggerSabine Strehl