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3D Genome Analysis Identifies Enhancer Hijacking Mechanism for High-Risk Factors in Human T-Lineage Acute Lymphoblastic Leukemial (T-ALL)

ABSTRACT: The goals of this study are to determine whether alterations in the 3D genome organization are associated with the malignant transformation of T-ALL. We report integrated analyses of 3D genome alterations and differentially expressed genes (DEGs) in 18 newly diagnosed T-ALL patients and 4 healthy T cell controls. We found that 3D genome reorganization at the compartment, topologically associated domains (TAD), and loop levels in different subtypes of T-ALL. Alterations in the 3D genome were associated with nearly 45% of the upregulated genes in T-ALL. We also identified 34 novel translocations in the noncoding regions of the genome and 44 new loops formed between translocated chromosomes. These translocations can activate the expression of oncogenic transcription factors including HOXA11-A13 by “cis” or “trans” reorganization of chromatin structure. Our analysis demonstrated that T-ALLs with HOXA cluster overexpression were heterogeneous clinical entities, and ectopic expressions of the HOXA11-A13 genes, but not other genes in the HOXA cluster, were associated with immature phenotypes and poor outcomes. Our findings highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146901 | GEO | 2021/03/20

REPOSITORIES: GEO

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Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). 104 samples; Affymetrix U133A micro-arrays. Ninety two patients with T-ALL were diagnosed and treated at Saint-Louis hospital, Paris. Seven patients were studied at diagnosis and relapse (total 99 T-ALL samples). There were 56 children (median age 9 years old; range 1 to 16), and 36 adults (median age 27; range 17 to 66). Informed consent was obtained from the patients and/or relatives. T-ALL diagnosis was based on morphological and immunophenotypical criteria using flow cytometry and an extended monoclonal antibody panel. Using a combination of molecular cytogenetic and large-scale expression analysis in human T-ALL, we identified and characterized a new recurrent chromosomal translocation, targeting the major homeobox gene cluster HOXA and the TCRB locus. Specific quantitative PCR analysis showed that the expression of the whole HOXA gene cluster was dramatically dysregulated in the HOXA-rearranged cases, and also in MLL and CALM-AF10-related T-ALL cases, strongly suggesting that HOXA genes are oncogenic in these leukemias. Inclusion of HOXA-translocated cases in a general molecular portrait of 92 T-ALL based on large-scale expression analysis shows that this rearrangement defines a new homogeneous subgroup, which shares common biological networks with the TLX1 and TLX3-related cases. Since T-ALLs derive from T-cell progenitors, expression profiles of the distinct T-ALL subgroups were analyzed with respect to those of normal human thymic sub-populations. Inappropriate utilization or perturbation of specific molecular networks involved in thymic differentiation was detected. Moreover, we found a significant association between T-ALL oncogenic subgroups and ectopic expression of a limited set of genes, including several developmental genes, namely HOXA, TLX1, TLX3, NKX3-1, SIX6 and TFAP2C. These data strongly support the view that the abnormal expression of developmental genes, including the prototypical homeobox genes HOXA, is critical in T-ALL oncogenesis. Project Leader: FranC'ois Sigaux Institut Universitaire d'Hematologie Hopital Saint Louis, Paris, France Data submission: Fabien Petel

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3D Genome Analysis Identifies Enhancer Hijacking Mechanism for High-Risk Factors in Human T-Lineage Acute Lymphoblastic Leukemial (T-ALL)

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