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Project description: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.
| S-EPMC8647946 | biostudies-literature
Project description:B cell acute lymphoblastic leukemia (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/relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. Collectively, our data show that the chromatin state at diagnosis varies widely among patients. While the majority of peaks remained stable between diagnosis and relapse, a significant fraction were either lost or newly gained with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome are 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. We also discovered three novel, relapse-specific super-enhancers shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Our results support the role of the epigenome in driving clonal evolution and uncover new candidate pathways associated with relapse.
2020-12-21 | GSE156532 | GEO
Project description:B cell acute lymphoblastic leukemia (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/relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. Collectively, our data show that the chromatin state at diagnosis varies widely among patients. While the majority of peaks remained stable between diagnosis and relapse, a significant fraction were either lost or newly gained with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome are 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. We also discovered three novel, relapse-specific super-enhancers shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Our results support the role of the epigenome in driving clonal evolution and uncover new candidate pathways associated with relapse.
2020-12-21 | GSE156560 | GEO
Project description:B cell acute lymphoblastic leukemia (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/relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. Collectively, our data show that the chromatin state at diagnosis varies widely among patients. While the majority of peaks remained stable between diagnosis and relapse, a significant fraction were either lost or newly gained with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome are 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. We also discovered three novel, relapse-specific super-enhancers shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Our results support the role of the epigenome in driving clonal evolution and uncover new candidate pathways associated with relapse.
2020-12-21 | GSE156531 | GEO
Project description:Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Role in Drug Resistance
| PRJNA658345 | ENA
Project description:Leukemogenesis is considered to be a process by which a normal cell acquires new but aberrant identity in order to disseminate a malignant clonal population. Under this setting, the phenotype of the leukemic cells is identical to the leukemia-initiating cell in which the genetic insult is taking place. Thus, with some exceptions, B-cell and T-cell childhood leukemias are supposed to arise from B- or T-committed cells. In contrast, several recent studies have revealed that genetic alterations may act in a "hit-and-run" way in the cell-of-origin by imposing the tumor cell identity giving rise to either B-cell or T-cell leukemias. This novel mechanism of cell transformation is mediated by an epigenetic priming mechanism that is established by the initial genetic lesion. This initial hit might be unnecessary for the subsequent tumor evolution and conservation, being the epigenetic priming the engine for the tumor evolution.
| S-EPMC6652134 | biostudies-literature
Project description:Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Role in Drug Resistance [eRRBS]
| PRJNA658262 | ENA
Project description:Biomarkers are biological molecules found in body fluids or tissues, which can be considered as indications of a normal or abnormal process, or of a condition or disease. There are various types of biomarkers based on their application and molecular alterations. Treatment-sensitivity or drug resistance biomarkers include prognostic and predictive molecules with utmost importance in selecting appropriate treatment protocols and improving survival rates. Acute lymphoblastic leukemia (ALL) is the most prevalent hematological malignancy diagnosed in children with nearly 80% cure rate. Despite the favorable survival rates of childhood ALL (chALL), resistance to chemotherapeutic agents and, as a consequence, a dismal prognosis develops in a significant number of patients. Therefore, there are urgent needs to have robust, sensitive, and disease-specific molecular prognostic and predictive biomarkers, which could allow better risk classification and then better clinical results. In this article, we review the currently known drug resistance biomarkers, including somatic or germ line nucleic acids, epigenetic alterations, protein expressions and metabolic variations. Moreover, biomarkers with potential clinical applications are discussed.
| S-EPMC6978753 | biostudies-literature
Project description:High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. It is characterized by gain of chromosomes, typically +X, +4, +6, +10, +14, +17, +18, and +21,+21; little is known about additional genetic aberrations. Approximately 20% of the patients relapse; therefore it is clinically important to identify risk-stratifying markers. We used SNP array analysis to investigate a consecutive series of 74 cases of high hyperdiploid ALL. We show that the characteristic chromosomal gains are even more frequent than previously believed, indicating that karyotyping mistakes are common, and that almost 80% of the cases display additional abnormalities detectable by SNP array analysis. Subclonality analysis strongly implied that the numerical aberrations were primary and arose before structural events, suggesting that step-wise evolution of the leukemic clone is common. An association between duplication of 1q and +5 was seen (P = 0.003). Other frequent abnormalities included whole-chromosome uniparental isodisomies (wUPIDs) 9 and 11, gain of 17q not associated with isochromosome formation, extra gain of part of 21q, deletions of ETS variant 6 (ETV6), cyclin-dependent kinase inhibitor 2A (CKDN2A) and paired box 5 (PAX5), and PAN3 poly(A) specific ribonuclease subunit homolog (PAN3) microdeletions. Comparison of whole-chromosome and partial UPID9 suggested different pathogenetic outcomes, with the former not involving CDKN2A. Finally, two cases had partial deletions of AT rich interactive domain 5B (ARID5B), indicating that acquired as well as constitutional variants in this locus may be associated with pediatric ALL. Here we provide a comprehensive characterization of the genetic landscape of high hyperdiploid childhood ALL, including the heterogeneous pattern of secondary genetic events.
| S-EPMC3003126 | biostudies-literature
Project description:Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Role in Drug Resistance [ChIP-seq]
| PRJNA658349 | ENA