A novel gene fusion RUNX1/ZNF423 promotes leukemic relapse of NUP98-rearranged AML
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PROVIDER: PRJNA917704 | ENA |
REPOSITORIES: ENA
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Project description:Acute myeloid leukemia (AML) is characterized by serious aggressivity of high relapse risk and various molecular aberrations. Rearrangements involving NUP98 with multiple fusing partner genes in myeloid malignancies indicate dismal survival outcomes. Mechanisms contributing to subsequent aggressive progression and severe relapse risk of NUP98-rearranged AML remain undefined. Here we identified a novel oncogenic fusion RUNX1/ZNF423 in a relapse and refractory AML patient with NUP98/NSD1. And mice xenografted from the patient bearing both RUNX1/ZNF423 and NUP98/NSD1 display more severe engraftment levels than NUP98/NSD1 only. Mechanically, RUNX1/ZNF423 accompanied with NUP98/NSD1 recapitulated transcriptional signatures in hematopoietic differentiation blockage and altered amino acid metabolism pathway. Moreover, single-cell sequencing confirmed the coexistence of RUNX1/ZNF423 with NUP98/NSD1 in the same leukemic blast. Meanwhile, we also found that the coexistence of gene fusions in NUP98-rearranged AML was a significant phenomenon, which probably contributes to their worse clinical outcome. Finally, tailored intervention treatment based on ex vivo drug sensitivity testing is provided to this relapse and refractory AML patient and achieved favorable clinical response. Taken together, we not only identified a novel gene fusion RUNX1/ZNF423 with transforming potential detected in a NUP98-rearranged AML, but also achieved a deeper understanding into mechanisms contributing to disease relapse in AML.
2024-12-01 | GSE222098 | GEO
Project description:Acute myeloid leukemia (AML) is characterized by serious aggressivity of high relapse risk and various molecular aberrations. Rearrangements involving NUP98 with multiple fusing partner genes in myeloid malignancies indicate dismal survival outcomes. Mechanisms contributing to subsequent aggressive progression and severe relapse risk of NUP98-rearranged AML remain undefined. Here we identified a novel oncogenic fusion RUNX1/ZNF423 in a relapse and refractory AML patient with NUP98/NSD1. And mice xenografted from the patient bearing both RUNX1/ZNF423 and NUP98/NSD1 display more severe engraftment levels than NUP98/NSD1 only. Mechanically, RUNX1/ZNF423 accompanied with NUP98/NSD1 recapitulated transcriptional signatures in hematopoietic differentiation blockage and altered amino acid metabolism pathway. Moreover, single-cell sequencing confirmed the coexistence of RUNX1/ZNF423 with NUP98/NSD1 in the same leukemic blast. Meanwhile, we also found that the coexistence of gene fusions in NUP98-rearranged AML was a significant phenomenon, which probably contributes to their worse clinical outcome. Finally, tailored intervention treatment based on ex vivo drug sensitivity testing is provided to this relapse and refractory AML patient and achieved favorable clinical response. Taken together, we not only identified a novel gene fusion RUNX1/ZNF423 with transforming potential detected in a NUP98-rearranged AML, but also achieved a deeper understanding into mechanisms contributing to disease relapse in AML.
2024-12-01 | GSE221767 | GEO
Project description:A novel gene fusion RUNX1/ZNF423 promotes leukemic relapse of NUP98-rearranged AML [RNAseq]
| PRJNA915978 | ENA
Project description:We assessed lineage involvement by NUP98 translocations in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and T-cell acute lymphoblastic leukemia (T-ALL). Single cell analysis by FICTION (Fluorescence Immunophenotype and Interphase Cytogenetics as a Tool for Investigation of Neoplasms) showed that NUP98-translocations with various partners, i.e. NSD1, DDX10, RAP1GDS1, and LNP1, always affected a CD34+/CD133+ hematopoietic precursor. Interestingly, in MDS/AML myelomonocytes, erythroid cells, B- and T- lymphocytes belonged to the abnormal clone, while in T-ALL only CD7+/CD3+ cells were involved. The partner did not appear to play a major role in determining the leukemia phenotype as shown in AML and T-ALL with the same NUP98-RAP1GDS1 fusion. Additional hits, namely mutations of FLT3 and CEBPA in MDS/AML and mutation of NOTCH1 plus MYB duplication in T-ALL, were identified in leukemias with, respectively, myeloid or T-lymphoid phenotype. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples. Copy number and Copy neutral LOH analysis of with Affymetrix Cytogenetic 2.7 and Cytoscan HD SNP arrays was performed on 6 NUP98 rearranged leukemias.
2014-08-26 | E-GEOD-60733 | biostudies-arrayexpress
Project description:The dysregulation of plant homeodomain (PHD) fingers has been implicated in several human diseases, including cancer. In a subset of aggressive acute myeloid leukemia (AML), chromosomal translocations that involve nucleoporin 98 (NUP98), a component of the nuclear pore complex, and a PHD finger-containing protein, such as KDM5A/JARID1A, PHF23 and BPTF, generate potent oncoproteins (namely NUP98-KDM5A, NUP98-PHF23 and NUP98-BPTF; or together termed as NUP98-PHD fusions) that are able to arrest hematopoietic differentiation and induce acute myeloid leukemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukemogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukemic transformation. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98-PHD finger fusions. Disulfiram (DS), a small molecule compound that directly targets the PHD finger, shows anti-proliferation effects in AML cells expressing NUP98-PHD through the conserved inhibitory mechanism. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.
2020-07-13 | GSE146693 | GEO
Project description: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.
2025-01-31 | GSE269226 | GEO
Project description:Chromosomal translocations involving the nucleoporin 98 (NUP98) gene at chromosome 11p15 are found in pediatric and adult Acute Myeloid Leukemia (AML) patients, representing one of the most common genetic alterations in pediatric AMLs found in ~10% of these patients. Previous studies demonstrated that NUP98 fusion proteins interact with MLL1 (Mixed Lineage Leukemia 1 also known as KMT2A) protein complex, and colocalize with MLL1 on Hoxa/b cluster genes, supporting MLL1 as a molecular dependency in the NUP98-r leukemia. Importantly, recent work has validated an important role of the scaffold protein menin, which directly interacts with the N-terminus of MLL1, in the NUP98-r leukemia. Here, we explored the effect of combining our menin inhibitor MI-3454 with CDK6 or FLT3 kinase inhibitors in the NUP98-r leukemia models as a possible way to enhance the anti-leukemic effect.
2024-10-30 | GSE246783 | GEO
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 | GSE269216 | GEO
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 | GSE269224 | GEO
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 | GSE269221 | GEO