Shella Saint Fleur-Lominy, Perlmutter Cancer Center, NYU Langone Health, New York, New YorkDepartment of Medicine, NYU Langone Health, New York, New York
Nikki A. Evensen, Perlmutter Cancer Center, NYU Langone Health, New York, New York
Teena Bhatla, Department of Pediatrics, Children's Hospital of New Jersey at NBI, RWJBarnabas Health, Newark, New Jersey
Gunjan Sethia, Perlmutter Cancer Center, NYU Langone Health, New York, New York
Sonali Narang, Perlmutter Cancer Center, NYU Langone Health, New York, New York
Jun H. Choi, Department of Medicine, NYU Langone Health, New York, New York
Xiaotu Ma, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
Jun J. Yang, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
Stephen Kelly, Perlmutter Cancer Center, NYU Langone Health, New York, New York
Elizabeth Raetz, Perlmutter Cancer Center, NYU Langone Health, New York, New York,, Department of Pediatrics, NYU Health, New York, New York
Richard C. Harvey, University of New Mexico Comprehensive Cancer Center, Department of Pathology, University of New Mexico School of Medicine and Health Sciences Center, Albuquerque, New Mexico
Cheryl Willman, University of New Mexico Comprehensive Cancer Center, Department of Pathology, University of New Mexico School of Medicine and Health Sciences Center, Albuquerque, New Mexico
Mignon L. Loh, Department of Pediatrics, UCSF Benioff Children's Hospital, San Francisco, California
Stephen P. Hunger, Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
Patrick A. Brown, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland
Kylie M. Getz, Department of Physiology and Biophysics and Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York
Cem Meydan, Department of Physiology and Biophysics and Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York
Christopher E. Mason, Department of Physiology and Biophysics and Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York
Aristotelis Tsirigos, Perlmutter Cancer Center, NYU Langone Health, New York, New York. william.carroll@nyumc.org Aristotelis.Tsirigos@nyumc.orgDepartment of Pathology, NYU Langone Health, New York, New York
William Carroll, Perlmutter Cancer Center, NYU Langone Health, New York, New York. william.carroll@nyumc.org Aristotelis.Tsirigos@nyumc.org, Department of Pediatrics, NYU Health, New York, New York,Department of Pathology, NYU Langone Health, New York, New York

Document Type

Article

Publication Date

12-1-2020

Abstract

Although B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection, yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients, while the majority of peaks remained stable between diagnosis and relapse. Yet a significant fraction was either lost or newly gained, with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific superenhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse. SIGNIFICANCE: This study suggests a major role for epigenetic mechanisms in driving clonal evolution in B-ALL and identifies novel pathways associated with drug resistance.

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