Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA395477 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To compare the global gene expressions between KLF4-expressed AML cells and albendazole-treated AML cells, we conducted gene expression arrays in THP-1 cells lentivirally-transduced with doxycycline-inducible KLF4 or in THP-1 cells treated with albendazole in different concentrations. We identified that albendazole induces prominent differentiation in THP-1 cells through up-regulating KLF4 and DPYSL2A expressions. Considering the guaranteed safety and tolerability of albendazole in humans, this drug could easily be repositioned to AML patients once its anti-tumor efficacy is clarified.
2021-03-09 | GSE101784 | GEO
Project description:Role of DPYSL2A in KLF4-mediated monocytic differentiation in AML cells
| PRJNA395350 | ENA
Project description:MicroRNAs (miRNAs) play a pivotal role in the regulation of hematopoiesis and development of leukemia. Great interest emerged in modulating miRNA expression for therapeutic purposes. In order to identify miRNAs, which specifically suppress leukemic growth of AML with t(8;21), inv(16) or MLL-rearrangement by inducing differentiation, we conducted a miRNA expression profiling in a cohort of 90 cytogenetically characterized, de novo pediatric AML cases. Four miRNAs, specifically downregulated in MLL-rearranged, t(8;21) or inv(16) AMLs, were characterized by their tumor suppressive properties in cell lines representing those respective cytogenetic groups. Among those, forced expression of miR-9 reduced leukemic growth and induced monocytic differentiation of t(8;21) AML cell lines in vitro and in vivo. The tumor suppressive functions of miR-9 were specifically restricted to AML cell lines and primary leukemic blasts with t(8;21). On the other hand, these functions were not evident in AML blasts from patients with MLL-rearrangements. We showed that miR-9 exerts its effects through the cooperation with let-7 to repress the oncogenic LIN28B/HMGA2 axis. Thus, miR-9 is a tumor suppressor-miR which acts in a stringent cell context-dependent manner. In order to identify miRNAs, which specifically suppress leukemic growth of AML with t(8;21) (n=21), inv(16) (n=17) or MLL-rearrangement (n=35) by inducing differentiation, we conducted a miRNA expression profiling in a cohort of 90 cytogenetically characterized, de novo pediatric AML cases, which also included 12 t(15;17) and 5 t(7;12) samples.
2014-01-01 | E-GEOD-52541 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) play a pivotal role in the regulation of hematopoiesis and development of leukemia. Great interest emerged in modulating miRNA expression for therapeutic purposes. In order to identify miRNAs, which specifically suppress leukemic growth of AML with t(8;21), inv(16) or MLL-rearrangement by inducing differentiation, we conducted a miRNA expression profiling in a cohort of 90 cytogenetically characterized, de novo pediatric AML cases. Four miRNAs, specifically downregulated in MLL-rearranged, t(8;21) or inv(16) AMLs, were characterized by their tumor suppressive properties in cell lines representing those respective cytogenetic groups. Among those, forced expression of miR-9 reduced leukemic growth and induced monocytic differentiation of t(8;21) AML cell lines in vitro and in vivo. The tumor suppressive functions of miR-9 were specifically restricted to AML cell lines and primary leukemic blasts with t(8;21). On the other hand, these functions were not evident in AML blasts from patients with MLL-rearrangements. We showed that miR-9 exerts its effects through the cooperation with let-7 to repress the oncogenic LIN28B/HMGA2 axis. Thus, miR-9 is a tumor suppressor-miR which acts in a stringent cell context-dependent manner.
2014-01-01 | GSE52541 | GEO
Project description:Acute myeloid leukemia (AML) is a heterogeneous malignancy rooted in hematopoietic stem cell dysregulation. Despite therapeutic advances, clinical outcomes remain unsatisfactory. Here, we identify KLF4, a zinc-finger (ZnF) transcription factor with previously reported context-dependent roles in hematologic malignancies, as a negative regulator of AML proliferation. Mechanistically, KLF4 interacts with the MLL3 histone methyltransferase complex, comprising MLL3, WDR5, RBBP5 and ASH2L. KLF4 engages the catalytic subunit MLL3 and the allosteric regulator ASH2L through its ZnF and transrepression (TRD) domains, thereby activating transcription of the tumor suppressor gene NRBP2. Furthermore, integrated transcriptional analysis revealed TNIK as a convergent effector of the KLF4–NRBP2 tumor-suppressive circuit in acute myeloid leukemia. Pharmacological blockade of TNIK with the selective small-molecule inhibitor TNIK-IN-1 selectively impaired leukemic cell proliferation while sparing normal hematopoiesis. Consequently, our findings reveal a previously unrecognized KLF4–MLL3 complex–NRBP2 transcriptional axis that suppresses AML survival through TNIK, highlighting a potential therapeutic strategy for AML.
2026-08-15 | GSE328227 | GEO
Project description:Acute myeloid leukemia (AML) is a heterogeneous malignancy rooted in hematopoietic stem cell dysregulation. Despite therapeutic advances, clinical outcomes remain unsatisfactory. Here, we identify KLF4, a zinc-finger (ZnF) transcription factor with previously reported context-dependent roles in hematologic malignancies, as a negative regulator of AML proliferation. Mechanistically, KLF4 interacts with the MLL3 histone methyltransferase complex, comprising MLL3, WDR5, RBBP5 and ASH2L. KLF4 engages the catalytic subunit MLL3 and the allosteric regulator ASH2L through its ZnF and transrepression (TRD) domains, thereby activating transcription of the tumor suppressor gene NRBP2. Furthermore, integrated transcriptional analysis revealed TNIK as a convergent effector of the KLF4–NRBP2 tumor-suppressive circuit in acute myeloid leukemia. Pharmacological blockade of TNIK with the selective small-molecule inhibitor TNIK-IN-1 selectively impaired leukemic cell proliferation while sparing normal hematopoiesis. Consequently, our findings reveal a previously unrecognized KLF4–MLL3 complex–NRBP2 transcriptional axis that suppresses AML survival through TNIK, highlighting a potential therapeutic strategy for AML.
2026-08-15 | GSE328080 | GEO
Project description:Acute myeloid leukemia (AML) is a heterogeneous malignancy rooted in hematopoietic stem cell dysregulation. Despite therapeutic advances, clinical outcomes remain unsatisfactory. Here, we identify KLF4, a zinc-finger (ZnF) transcription factor with previously reported context-dependent roles in hematologic malignancies, as a negative regulator of AML proliferation. Mechanistically, KLF4 interacts with the MLL3 histone methyltransferase complex, comprising MLL3, WDR5, RBBP5 and ASH2L. KLF4 engages the catalytic subunit MLL3 and the allosteric regulator ASH2L through its ZnF and transrepression (TRD) domains, thereby activating transcription of the tumor suppressor gene NRBP2. Furthermore, integrated transcriptional analysis revealed TNIK as a convergent effector of the KLF4–NRBP2 tumor-suppressive circuit in acute myeloid leukemia. Pharmacological blockade of TNIK with the selective small-molecule inhibitor TNIK-IN-1 selectively impaired leukemic cell proliferation while sparing normal hematopoiesis. Consequently, our findings reveal a previously unrecognized KLF4–MLL3 complex–NRBP2 transcriptional axis that suppresses AML survival through TNIK, highlighting a potential therapeutic strategy for AML.
2026-08-15 | GSE306746 | GEO
Project description:To compare the global gene expressions in between KLF4- and DPYSL2A-expressed AML cells, we conducted gene expression arrays in THP-1 cells lentivirally-transduced with doxycycline-inducible KLF4 or DPYSL2A. We identified the pivotal role of KLF4-DPYSL2A axis in differentiating AML cells, which could be theraputically-tageted in conventional therapy-resistant AML patients.
2020-05-31 | GSE101751 | GEO
Project description:Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. Kinome profiling of Molm14 cells, both NRAS WT and NRAS G12C, both treatment-naive and venetoclax resistant, additionally shows RAS upregulation with venetoclax resistance. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition.
2026-06-15 | PXD068585 | Pride
Project description:Resistance to venetoclax-based therapy in acute myeloid leukemia (AML) includes genetic (i.e., mutations in N/KRAS, FLT3-ITD, TP53) and phenotypic (i.e., monocytic differentiation) features. Whether monocytic differentiation contributes to clinical venetoclax resistance secondary to a genetic bias remains unknown. This multimodal, multicenter, international analysis inclusive of 678 patients comprehensively characterized the prognostic role of monocytic differentiation in AML patients treated with hypomethylating agents combined with venetoclax. AML genetics and monocytic differentiation (HR: 1.89, 95% CI: 1.35-2.66, p < 0.001) in NPM1 wild-type cases correlated with an increased risk of death. Clustering of centralized quantitative multiparameter flow cytometry data, evaluation of RNA sequencing-derived AML maturation stage, and single-cell proteogenomics linked driver mutations with AML phenotype and anti-apoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and anti-apoptotic protein expression highlights the complementary role these factors impart following venetoclax-based therapy.
2025-05-14 | GSE296535 | GEO