Project description:Genome-wide DNA methylation profiling of 4 gliomas with EWSR1-BEND fusions with histologic features resembling astroblastoma. The Illumina Infinium EPIC 850k Human DNA Methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpG sites of genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissue of 4 gliomas with EWSR1-BEND2 fusions.
Project description:Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a challenging brain cancer of unknown cellular origin, is associated with diverse in-frame gene fusions, including MN1:BEND2 and MN1:CXXC5. However, it remains unclear if these gene fusions contribute to tumorigenesis. Here, we show that the two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognized similar DNA motifs, suggesting a convergence on downstream gene regulation. Expressing MN1:BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM, and acquisition of an ABM-associated transcriptional signature. In stark contrast, MN1:BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type specific malignancy is dependent on Olig2 expression. Mechanistically, both ABM-associated fusion proteins (MN1:BEND2 and MN1:CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggests that distinct ABM-associated fusions upregulate shared transcriptional networks, thereby disrupting the normal development of ventral telencephalon neural progenitors and culminating in oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.
Project description:Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a challenging brain cancer of unknown cellular origin, is associated with diverse in-frame gene fusions, including MN1:BEND2 and MN1:CXXC5. However, it remains unclear if these gene fusions contribute to tumorigenesis. Here, we show that the two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognized similar DNA motifs, suggesting a convergence on downstream gene regulation. Expressing MN1:BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM, and acquisition of an ABM-associated transcriptional signature. In stark contrast, MN1:BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type specific malignancy is dependent on Olig2 expression. Mechanistically, both ABM-associated fusion proteins (MN1:BEND2 and MN1:CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggests that distinct ABM-associated fusions upregulate shared transcriptional networks, thereby disrupting the normal development of ventral telencephalon neural progenitors and culminating in oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.
Project description:Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a challenging brain cancer of unknown cellular origin, is associated with diverse in-frame gene fusions, including MN1:BEND2 and MN1:CXXC5. However, it remains unclear if these gene fusions contribute to tumorigenesis. Here, we show that the two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognized similar DNA motifs, suggesting a convergence on downstream gene regulation. Expressing MN1:BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM, and acquisition of an ABM-associated transcriptional signature. In stark contrast, MN1:BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type specific malignancy is dependent on Olig2 expression. Mechanistically, both ABM-associated fusion proteins (MN1:BEND2 and MN1:CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggests that distinct ABM-associated fusions upregulate shared transcriptional networks, thereby disrupting the normal development of ventral telencephalon neural progenitors and culminating in oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.
Project description:Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a challenging brain cancer of unknown cellular origin, is associated with diverse in-frame gene fusions, including MN1:BEND2 and MN1:CXXC5. However, it remains unclear if these gene fusions contribute to tumorigenesis. Here, we show that the two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognized similar DNA motifs, suggesting a convergence on downstream gene regulation. Expressing MN1:BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM, and acquisition of an ABM-associated transcriptional signature. In stark contrast, MN1:BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type specific malignancy is dependent on Olig2 expression. Mechanistically, both ABM-associated fusion proteins (MN1:BEND2 and MN1:CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggests that distinct ABM-associated fusions upregulate shared transcriptional networks, thereby disrupting the normal development of ventral telencephalon neural progenitors and culminating in oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.
Project description:Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a challenging brain cancer of unknown cellular origin, is associated with diverse in-frame gene fusions, including MN1:BEND2 and MN1:CXXC5. However, it remains unclear if these gene fusions contribute to tumorigenesis. Here, we show that the two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognized similar DNA motifs, suggesting a convergence on downstream gene regulation. Expressing MN1:BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM, and acquisition of an ABM-associated transcriptional signature. In stark contrast, MN1:BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type specific malignancy is dependent on Olig2 expression. Mechanistically, both ABM-associated fusion proteins (MN1:BEND2 and MN1:CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggests that distinct ABM-associated fusions upregulate shared transcriptional networks, thereby disrupting the normal development of ventral telencephalon neural progenitors and culminating in oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.
Project description:Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a challenging brain cancer of unknown cellular origin, is associated with diverse in-frame gene fusions, including MN1:BEND2 and MN1:CXXC5. However, it remains unclear if these gene fusions contribute to tumorigenesis. Here, we show that the two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognized similar DNA motifs, suggesting a convergence on downstream gene regulation. Expressing MN1:BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM, and acquisition of an ABM-associated transcriptional signature. In stark contrast, MN1:BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type specific malignancy is dependent on Olig2 expression. Mechanistically, both ABM-associated fusion proteins (MN1:BEND2 and MN1:CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggests that distinct ABM-associated fusions upregulate shared transcriptional networks, thereby disrupting the normal development of ventral telencephalon neural progenitors and culminating in oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.
Project description:Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a challenging brain cancer of unknown cellular origin, is associated with diverse in-frame gene fusions, including MN1:BEND2 and MN1:CXXC5. However, it remains unclear if these gene fusions contribute to tumorigenesis. Here, we show that the two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognized similar DNA motifs, suggesting a convergence on downstream gene regulation. Expressing MN1:BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM, and acquisition of an ABM-associated transcriptional signature. In stark contrast, MN1:BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type specific malignancy is dependent on Olig2 expression. Mechanistically, both ABM-associated fusion proteins (MN1:BEND2 and MN1:CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggests that distinct ABM-associated fusions upregulate shared transcriptional networks, thereby disrupting the normal development of ventral telencephalon neural progenitors and culminating in oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.