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Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [RNA-Seq]

ABSTRACT: We found NUP98 fusions activate Hoxb-associated lncRNA, HoxBlinc that occupies and regulates homeotic/oncogenic topologically associated domain (TAD) in malignant hematopoiesis. Aberration of HoxBlinc led to recruitment of MLL1 complex , altered chromatin landscape (both H3K4me3 and chromatin accessibility), and HOX/homeotic gene activatiion in NUP98-PHF23 fusion driven leukemia and HoxBlinc -Tg models. Conversely, eliminated HoxBlinc in NUP98 fusion-driven leukemic cells resulted in loss of Hoxblinc binding, TAD integrity, recruitment of MLL complex, and MLL driven H3K4me3 and chromatin accessibility within the HoxBlinc defined domain in a CTCF independent manner, leading to inhibiting homeotic/leukemic oncogenes and mitigating NUP98 fusion-driven leukemia in xenografted mouse models. Thus, our studies revealed a CTCF independent role of HoxBlinc in leukemic TAD organization and oncogenic gene regulatory networks in NUP98-fusion related leukemia.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE269226 | GEO | 2025/01/31

REPOSITORIES: GEO

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Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [CTCF-HiChIP-seq]

Project description:We found NUP98 fusions activate Hoxb-associated lncRNA, HoxBlinc that occupies homeotic/oncogenic topologically associated domain (TAD) boundaries in malignant hematopoiesis. Aberration of HoxBlinc led to recruitment of MLL1 complex and reorganization of homeotic/oncogenicTADs that enhanced chromatin accessibilities and aberrantly activated homeotic/hematopoietic oncogenes defined by Hoxblinc chromatin occupancies in NUP98-PHF23 related murine leukemia cells. Eliminated HoxBlinc in NUP98 fusion-driven leukemic cells resulted in loss of Hoxblinc binding, TAD integrity, recruitment of MLL complex, and MLL driven H3K4me3 and chromatin accessibility within the HoxBlinc defined domain in a CTCF independent manner, leading to inhibiting homeotic/leukemic oncogenes and mitigating NUP98 fusion-driven leukemia in xenografted mouse models. Moreover, overexpression of HoxBlinc in mouse bone marrow hematopoietic compartment developed multiple leukemia resembling NUP98-PHF23 knock-in mice via enhancing HoxBlinc binding and TAD formation to transcriptionally expanding HS/PC and myeloid/lymphoid subpopulations leading to leukemogenesis. Our studies reveal a CTCF independent role of HoxBlinc in leukemic TAD organization and oncogenic gene regulatory networks in NUP98-fusion related leukemia.

2025-01-31 | GSE283303 | GEO

Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [ChIRP-seq]

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Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [CUT&Run]

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Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [scRNA-Seq]

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Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [Hi-C]

2025-01-31 | GSE269218 | GEO

Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [ChIP-Seq]

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Hoxblinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98 fusion transformed leukemia [ATAC-Seq]

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MLL is essential for NUP98-HOXA9-induced leukemia

Project description:Rearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in acute myeloid leukemia and myelodysplastic syndromes. This study demonstrates that the second FG repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with MLL via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited. Molecular analyses indicate that MLL is important for the recruitment of NUP98-HOXA9 to the HOXA locus and for NUP98-HOXA9-induced HOXA gene expression. Our data indicate that MLL is crucial for NUP98-HOXA9 leukemia initiation.

2017-02-28 | GSE93923 | GEO

Global mouse gene expression data from NUP98-NSD1/FLT3-ITD AML samples and Normal Wild Type whole bone marrow and Normal Wild Type lineage negative bone marrow samples assessed by Bulk RNA-Seq.

Project description:Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy driven largely by gene mutations and epigenetic modifications. The Nucleoporin 98kDa (NUP98) gene is a component of the nuclear pore complex that also plays a role as an intranuclear transcription scaffold. Fusion genes involving NUP98 have been recognized in a wide array of hematologic malignancy, most commonly AML4. Among over 30 partner genes known to be fused to NUP98 in human leukemia, NSD1 (for Nuclear receptor-binding SET Domain protein 1) (NSD1) is the most common. Patients with NUP98::NSD1 gene fusions have a poor prognosis, and the leukemic blasts frequently have an internal tandem duplication (ITD) of the FMS-related tyrosine kinase 3 gene (FLT3) gene accompanying the NUP98::NSD1 fusion. Previous reports have utilized BM transduction with retroviral vectors followed by transplantation into recipient mice to model AML driven by a NUP98::NSD1 fusion. Given that genetically engineered mice offer certain advantages over retroviral transduction models, such as consistent transgene expression and integration effects, lack of ionizing radiation, and transferability between investigators, we generated NUP98::Nsd1 transgenic mice.

2023-07-12 | GSE229501 | GEO

Tetraspanin 3 is Required for the Development and Propagation of Acute Myelogenous Leukemia

Project description:Msi2 is a critical regulatior of myeoid leukemia, and these data identify genes that are changed following Msi2 deletion in bcCML and de novo AML stem cells. Leukemic stem cells were extracted from wild-type and Msi2 mutant MLL-AF9 driven AML and BCR-ABL/NUP98-HOXA9 driven bcCML, in triplicate. RNA was extracted and hybridized on Affymetrix microarrays. The mouse strain was a genetic trap Msi2 mutant made by Center for Animal Resources and Development (CARD) of Kumamoto University. They call their strain B6;CB-Msi2Gt(pU-21T)2Imeg, see also http://cardb.cc.kumamoto-u.ac.jp/transgenic/strainsDetailAction.do?strainId=834

2015-06-04 | E-GEOD-69512 | biostudies-arrayexpress

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