UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients

Christen, F; Hoyer, K; Yoshida, K; Hou, H-A; Waldhueter, N; Heuser, M; Hills, RK; ... Damm, F; + view all (2019) Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood 10.1182/blood-2018-05-852822. (In press).

[img] Text
Gale_Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21). An international study on 331 patients_AAM.pdf - ["content_typename_Accepted version" not defined]
Access restricted to UCL open access staff until 5 January 2020.

Download (6MB)

Abstract

Acute myeloid leukemia (AML) with t(8;21)(q22;q22) is characterized by considerable clinical and biological heterogeneity leading to relapse in up to 40%. We sequenced coding regions or hotspot areas of 66 recurrently mutated genes in a cohort of 331 t(8;21) patients. At least one mutation in addition to t(8;21) was identified in 95% with a mean of 2.2 driver mutations per patient. Recurrent mutations occurred in genes related to RAS/RTK signaling (63.4%), epigenetic regulators (45%), cohesin complex (13.6%), MYC signaling (10.3%), and the spliceosome (7.9%). Our study identified mutations in previously unappreciated genes GIGY2F, DHX15, and G2E3. Based on high mutant levels, pairwise precedence, and stability at relapse, epigenetic regulator mutations were likely to occur before signaling mutations. In 34% of RAS/RTK^{mutated} patients, we identified multiple mutations in the same pathway. Deep sequencing (≈42,000x) of 126 mutations in 62 CR samples from 56 patients identified 16 persisting mutations in 12 patients, of whom five lacked RUNX1-RUNX1T1 in qPCR analysis. KIT^{high} mutations defined by a mutant level ≥25% were associated with inferior relapse-free survival (HR=1.96; 95%-CI 1.22-3.15; P=.005). Together with age and white blood cell counts, JAK2, FLT3-ITD^{high}, and KIT^{high} mutations were identified as significant prognostic factors for overall survival in multivariate analysis. Whole-exome sequencing was performed on 19 paired diagnosis, remission, and relapse trios. Exome-wide analysis showed an average of 16 mutations with signs of substantial clonal evolution. Based on the resemblance of diagnosis and relapse pairs, genetically stable (n=13) and unstable (n=6) subgroups could be identified.

Type: Article
Title: Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients
Location: United States
DOI: 10.1182/blood-2018-05-852822
Publisher version: https://doi.org/10.1182/blood-2018-05-852822
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: AML, core binding factor, clonal heterogeneity, ASXL2, ZBTB7A
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/10066337
Downloads since deposit
3Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item