Dataset Information

Establishment of the lymphoid ETS-code reveals deregulated ETS genes in Hodgkin lymphoma.

ABSTRACT: The human family of ETS transcription factors numbers 28 genes which control multiple aspects of development, notably the differentiation of blood and immune cells. Otherwise, aberrant expression of ETS genes is reportedly involved in forming leukemia and lymphoma. Here, we comprehensively mapped ETS gene activities in early hematopoiesis, lymphopoiesis and all mature types of lymphocytes using public datasets. We have termed the generated gene expression pattern lymphoid ETS-code. This code enabled identification of deregulated ETS genes in patients with lymphoid malignancies, revealing 12 aberrantly expressed members in Hodgkin lymphoma (HL). For one of these, ETS gene ETV3, expression in stem and progenitor cells in addition to that in developing and mature T-cells was mapped together with downregulation in B-cell differentiation. In contrast, subsets of HL patients aberrantly overexpressed ETV3, indicating oncogenic activity in this B-cell malignancy. Analysis of ETV3-overexpressing HL cell line SUP-HD1 demonstrated genomic duplication of the ETV3 locus at 1q23, GATA3 as mutual activator, and suppressed BMP-signalling as mutual downstream effect. Additional examination of the neighboring ETS genes ETS1 and FLI1 revealed physiological activities in B-cell development and aberrant downregulation in HL patient subsets. SUP-HD1 showed genomic loss on chromosome 11, del(11)(q22q25), targeting both ETS1 and FLI1, underlying their downregulation. Furthermore, in the same cell line we identified PBX1-mediated overexpression of RIOK2 which inhibited ETS1 and activated JAK2 expression. Collectively, we codified normal ETS gene activities in lymphopoiesis and identified oncogenic ETS members in HL.

SUBMITTER: Nagel S

PROVIDER: S-EPMC10332584 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Establishment of the lymphoid ETS-code reveals deregulated ETS genes in Hodgkin lymphoma.

Nagel Stefan S Meyer Corinna C Pommerenke Claudia C

PloS one 20230710 7

The human family of ETS transcription factors numbers 28 genes which control multiple aspects of development, notably the differentiation of blood and immune cells. Otherwise, aberrant expression of ETS genes is reportedly involved in forming leukemia and lymphoma. Here, we comprehensively mapped ETS gene activities in early hematopoiesis, lymphopoiesis and all mature types of lymphocytes using public datasets. We have termed the generated gene expression pattern lymphoid ETS-code. This code ena ...[more]

PMID: 37428779

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Project description:Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation and are grouped into classes and subclasses according to sequence similarities. Here, we analyzed the activities of the 20 members strong TALE homeobox gene class in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells (ILC). The resultant expression pattern comprised eleven genes and which we termed TALE-code enables discrimination of normal and aberrant activities of TALE homeobox genes in lymphoid malignancies. Subsequent expression analysis of TALE homeobox genes in public datasets of Hodgkin lymphoma (HL) patients revealed overexpression of IRX3, IRX4, MEIS1, MEIS3, PBX1, PBX4 and TGIF1. As paradigm we focused on PBX1 which was deregulated in about 17% HL patients. Normal PBX1 expression was restricted to hematopoietic stem cells and progenitors of T-cells and ILCs but absent in B-cells, reflecting its roles in stemness and early differentiation. HL cell line SUP-HD1 expressed enhanced PBX1 levels and served as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line therein showed a gain of the PBX1 locus at 1q23 which may underlie its aberrant expression. Comparative expression profiling analyses of HL patients and cell lines followed by knockdown experiments revealed NFIB and TLX2 as target genes activated by PBX1. HOX proteins operate as cofactors of PBX1. Accordingly, our data showed that HOXB9 overexpressed in HL coactivated TLX2 but not NFIB while activating TNFRSF9 without PBX1. Further downstream analyses showed that TLX2 activated TBX15 which operated anti-apoptotically. Taken together, we discovered a lymphoid TALE-code and identified an aberrant network around deregulated TALE homeobox gene PBX1 which may disturb B-cell differentiation in HL by reactivation of progenitor-specific genes. These findings may provide the framework for future studies to exploit possible vulnerabilities of malignant cells in therapeutic scenarios.

Project description:T-box genes encode transcription factors which control basic processes in development of several tissues including cell differentiation in the hematopoietic system. Here, we analyzed the physiological activities of all 17 human T-box genes in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells. The resultant expression pattern comprised six genes, namely EOMES, MGA, TBX1, TBX10, TBX19 and TBX21. We termed this gene signature TBX-code which enables discrimination of normal and aberrant activities of T-box genes in lymphoid malignancies. Accordingly, expression analysis of T-box genes in Hodgkin lymphoma (HL) patients using a public profiling dataset revealed overexpression of EOMES, TBX1, TBX2, TBX3, TBX10, TBX19, TBX21 and TBXT while MGA showed aberrant downregulation. Analysis of T-cell acute lymphoid leukemia patients indicated aberrant overexpression of six T-box genes while no deregulated T-box genes were detected in anaplastic large cell lymphoma patients. As a paradigm we focused on TBX3 which was ectopically activated in about 6% of HL patients analyzed. Normally, TBX3 is expressed in tissues like lung, adrenal gland and retina but not in hematopoiesis. HL cell line KM-H2 expressed enhanced TBX3 levels and was used as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line showed focal amplification of the TBX3 locus at 12q24 which may underlie its aberrant expression. In addition, promoter analysis and comparative expression profiling of HL cell lines followed by knockdown experiments revealed overexpressed transcription factors E2F4 and FOXC1 and chromatin modulator KDM2B as functional activators. Furthermore, we identified repressed target genes of TBX3 in HL including CDKN2A, NFKBIB and CD19, indicating its respective oncogenic function in proliferation, NFkB-signaling and B-cell differentiation. Taken together, we have revealed a lymphoid TBX-code and used it to identify an aberrant network around deregulated T-box gene TBX3 in HL which promotes hallmark aberrations of this disease. These findings provide a framework for future studies to evaluate deregulated T-box genes in lymphoid malignancies.

Dataset Information

Establishment of the lymphoid ETS-code reveals deregulated ETS genes in Hodgkin lymphoma.

Publications

Establishment of the lymphoid ETS-code reveals deregulated ETS genes in Hodgkin lymphoma.

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