Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia.
Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.
Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.
Sheng
S
Li
Division of Hematology-Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Francine E
FE
Garrett-Bakelman
Leukemia Service, Department of Medicine, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Stephen S
SS
Chung
Erasmus University Medical Center, Department of Hematology, Rotterdam, the Netherlands.
Mathijs A
MA
Sanders
Leukemia Service, Department of Medicine, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Todd
T
Hricik
Leukemia Service, Department of Medicine, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Franck
F
Rapaport
Leukemia Service, Department of Medicine, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Jay
J
Patel
Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, UK.
Richard
0000-0001-9333-5296
R
Dillon
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, New York, USA.
Priyanka
P
Vijay
Center for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.|School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Department of Hematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Anna L
AL
Brown
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Alexander E
AE
Perl
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Joy
J
Cannon
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Lars
L
Bullinger
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Selina
S
Luger
University of Rochester Medical Center, Rochester, New York, USA.
Michael
M
Becker
Center for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.|Department of Hematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
Ian D
ID
Lewis
Department of Hematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
Luen Bik
LB
To
Erasmus University Medical Center, Department of Hematology, Rotterdam, the Netherlands.
Ruud
R
Delwel
Erasmus University Medical Center, Department of Hematology, Rotterdam, the Netherlands.
Bob
B
Löwenberg
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Hartmut
H
Döhner
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Konstanze
K
Döhner
Division of Hematology-Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Monica L
ML
Guzman
Division of Hematology-Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Duane C
DC
Hassane
Division of Hematology-Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Gail J
GJ
Roboz
Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, UK.
David
D
Grimwade
Erasmus University Medical Center, Department of Hematology, Rotterdam, the Netherlands.
Peter J M
PJ
Valk
Center for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.|School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Department of Hematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Richard J
RJ
D'Andrea
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Martin
M
Carroll
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Christopher Y
CY
Park
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Donna
0000-0003-2566-3145
D
Neuberg
Leukemia Service, Department of Medicine, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Ross
R
Levine
Division of Hematology-Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Ari M
AM
Melnick
Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.|The Feil Family Brain and Mind Research Institute, New York, New York, USA.
Christopher E
CE
Mason
D000328:Adult; D000483:Alleles; D018899:CpG Islands; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D015996:Survival Rate
D003596:Cytosine