A Preclinical Model of Human Acute Myeloid Leukemia with an Autologous Immune System for Studying Mechanisms of Tumorigenesis and Immunotherapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE79927 | GEO | 2019/03/31
REPOSITORIES: GEO
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Project description:Purpose: To understand the molecular mechanisms underlying NPM1c-mediated tumorigenesis by comparing the transcriptome of de novo generated bulk human leukemic cells and leukemic stem cells
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Project description:Mutations in the NPM1 gene are found in more than 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal (NoLS) and create a novel nuclear export signal (NES), leading to cytoplasmic displacement of the protein (NPM1c). NPM1c mutations prime hematopoietic progenitors to leukemic transformation, but their precise molecular consequences remain elusive. Here, we first examined the effects of isolated NPM1c mutations on the global proteome of pre-leukemic hematopoietic progenitors using a conditional knock-in Npm1cA/+ mouse model. We discovered a significant depletion of many factors involved in the ribosome biogenesis pathway which, importantly, persists in NPM1-mutant AML patients. Next, we found that pre-leukemic Npm1cA/+ cells display higher sensitivity to Actinomycin D (ActD) and other RNA pol I inhibitors when compared to wild-type Npm1+/+ cells. Combination treatment with ActD and Venetoclax inhibited the growth and colony forming ability of pre-leukemic and leukemic NPM1c+ cells and low-dose ActD treatment was able to re-sensitize resistant NPM1c+ cells to Venetoclax. Finally, by contrasting our findings with data from CRISPR drop-out screens, we identified and validated TSR3, a ribosome maturation factor of the 40S ribosomal subunit whose knock-out preferentially inhibited the proliferation of NPM1c+ AML cells by activating a p53-dependent response. Similar to low-dose ActD treatment, TSR3 depletion could partially restore sensitivity to Venetoclax in therapy-resistant NPM1c+ AML models.
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Project description:NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c). NPM1 mutations are founding genetic lesions, however it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in downregulation of homeobox (HOX) genes, and differentiation and cell growth arrest of AML cells. Additionally, we show that HOX downregulation is the earliest transcriptional event following the loss of NPM1c from the cytoplasm, preceding and promoting differentiation. Finally, we show that XPO1 inhibition efficiently relocalizes NPM1c to the nucleus, enables differentiation and prolongs survival of Npm1c+ leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.
2018-08-06 | GSE111179 | GEO
Project description:NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c). NPM1 mutations are founding genetic lesions, however it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in downregulation of homeobox (HOX) genes, and differentiation and cell growth arrest of AML cells. Additionally, we show that HOX downregulation is the earliest transcriptional event following the loss of NPM1c from the cytoplasm, preceding and promoting differentiation. Finally, we show that XPO1 inhibition efficiently relocalizes NPM1c to the nucleus, enables differentiation and prolongs survival of Npm1c+ leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.
2018-08-06 | GSE111178 | GEO
Project description:C-terminal mutation of Nucleophosmin 1 (NPM1C+) was thought to be a primary driving event that reprograms leukemic-associated transcription program to transform hematopoietic stem and progenitor cells (HS/PCs). However, molecular mechanism underlying NPM1C+-driven leukemogenesis remain elusive. Here, we reported that NPM1C+ reprograms MIZ-1/MYC regulatory axis by altering NPM1-associated CTCF-driven topologically associated domains (TADs) that switched the balance of MIZ1 interaction with co-repressors MYC/G9A and coactivator p300 to control cell cycle progress and myeloid lineage-specific PU.1/CEBPa transcription networks. These alterations impaired hematopoietic cell cycle progression and myeloid differentiation. Knock-in of NPM1C+ in bone marrow HSPCs alters cell cycle regulators and myeloid master transcription factor (TF) TAD topology, chromatin accessibility, and gene regulation leading blockage of myeloid differentiation. Retention of NPM1 or reactivation of PU.1 or CEBPa within nucleus activates differentiation program by reorganizing TADs critical for myeloid TFs and cell cycle regulator, leading to blockage of NPM1C+-driven leukemogenesis. Thus, our data revealed that NPM1C+ reshapes CTCF-defined TAD topology to reprogram signature leukemic transcription program require for cell cycle progression and leukemic progression. Restoration of myeloid transcription program in nucleus reversed NPM1C+-driven transcription signature and promotes myeloid differentiation leading to mitigation of AML.
2023-08-09 | GSE208022 | GEO
Project description:Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability1-4. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), resulting in the change of the nucleolar localization signal into a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c)2,3,5. AMLs carrying this mutation have aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation6-8. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus causes downregulation of the HOXA genes, leading to the speculation that NPM1c directly regulates their transcription9-11. Here, we show that NPM1c binds to a subset of active gene promoters marked with high levels of H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts, including well-known leukemia-driving genes such as posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets IRX5 and NKX2-3. The binding of NPM1c on chromatin sustains active transcription of key target genes by maintaining high local-concentration of transcriptional complexes, including the Super Elongation Complex (SEC) and Menin/MLL1. NPM1c also maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Depletion of NPM1c causes histone deacetylation and the silencing of key leukemic genes, leading to cell differentiation and growth arrest. The export protein XPO1 plays a key role by tethering NPM1c onto chromatin. The combination of XPO1 inhibitors (e.g., Selinexor and Eltanexor) with the Menin inhibitor MI-3454 has a synergistic effect on inducing differentiation in both NPM1-mutated leukemia cell lines and PDX model. Together, these findings reveal the neomorphic function of NPM1c as transactivator for leukemic gene expression and open up potential avenues for therapeutic intervention.
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Project description:Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability1-4. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), resulting in the change of the nucleolar localization signal into a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c)2,3,5. AMLs carrying this mutation have aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation6-8. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus causes downregulation of the HOXA genes, leading to the speculation that NPM1c directly regulates their transcription9-11. Here, we show that NPM1c binds to a subset of active gene promoters marked with high levels of H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts, including well-known leukemia-driving genes such as posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets IRX5 and NKX2-3. The binding of NPM1c on chromatin sustains active transcription of key target genes by maintaining high local-concentration of transcriptional complexes, including the Super Elongation Complex (SEC) and Menin/MLL1. NPM1c also maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Depletion of NPM1c causes histone deacetylation and the silencing of key leukemic genes, leading to cell differentiation and growth arrest. The export protein XPO1 plays a key role by tethering NPM1c onto chromatin. The combination of XPO1 inhibitors (e.g., Selinexor and Eltanexor) with the Menin inhibitor MI-3454 has a synergistic effect on inducing differentiation in both NPM1-mutated leukemia cell lines and PDX model. Together, these findings reveal the neomorphic function of NPM1c as transactivator for leukemic gene expression and open up potential avenues for therapeutic intervention.
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Project description:Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability1-4. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), resulting in the change of the nucleolar localization signal into a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c)2,3,5. AMLs carrying this mutation have aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation6-8. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus causes downregulation of the HOXA genes, leading to the speculation that NPM1c directly regulates their transcription9-11. Here, we show that NPM1c binds to a subset of active gene promoters marked with high levels of H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts, including well-known leukemia-driving genes such as posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets IRX5 and NKX2-3. The binding of NPM1c on chromatin sustains active transcription of key target genes by maintaining high local-concentration of transcriptional complexes, including the Super Elongation Complex (SEC) and Menin/MLL1. NPM1c also maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Depletion of NPM1c causes histone deacetylation and the silencing of key leukemic genes, leading to cell differentiation and growth arrest. The export protein XPO1 plays a key role by tethering NPM1c onto chromatin. The combination of XPO1 inhibitors (e.g., Selinexor and Eltanexor) with the Menin inhibitor MI-3454 has a synergistic effect on inducing differentiation in both NPM1-mutated leukemia cell lines and PDX model. Together, these findings reveal the neomorphic function of NPM1c as transactivator for leukemic gene expression and open up potential avenues for therapeutic intervention.
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Project description:Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability1-4. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), resulting in the change of the nucleolar localization signal into a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c)2,3,5. AMLs carrying this mutation have aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation6-8. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus causes downregulation of the HOXA genes, leading to the speculation that NPM1c directly regulates their transcription9-11. Here, we show that NPM1c binds to a subset of active gene promoters marked with high levels of H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts, including well-known leukemia-driving genes such as posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets IRX5 and NKX2-3. The binding of NPM1c on chromatin sustains active transcription of key target genes by maintaining high local-concentration of transcriptional complexes, including the Super Elongation Complex (SEC) and Menin/MLL1. NPM1c also maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Depletion of NPM1c causes histone deacetylation and the silencing of key leukemic genes, leading to cell differentiation and growth arrest. The export protein XPO1 plays a key role by tethering NPM1c onto chromatin. The combination of XPO1 inhibitors (e.g., Selinexor and Eltanexor) with the Menin inhibitor MI-3454 has a synergistic effect on inducing differentiation in both NPM1-mutated leukemia cell lines and PDX model. Together, these findings reveal the neomorphic function of NPM1c as transactivator for leukemic gene expression and open up potential avenues for therapeutic intervention.
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