Similar Datasets
Project description:Combinatorial CRISPRko screening data in leukemia cell lines
2022-12-16 | GSE215347 | GEO
Project description:Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.
2022-12-16 | GSE215348 | GEO
Project description:Knockout of NuRD complex members in THP-1, Reh, and MV4-11 leukemia cell lines.
2022-12-16 | GSE214773 | GEO
Project description:THis is a simple ordinary differential equation model describing chemoimmunotherapy of chronic lymphocytic leukemia, including descriptions of the combinatorial effects of chemotherapy and adoptive cellular immunotherapy.
2024-09-02 | BIOMD0000000879 | BioModels
Project description:HSP90 inhibitors (HSP90i) have not entered routinely in the clinics, primarily due to the associated resistance via heat shock response (HSR) induction and dose limiting toxicity. In this study, we employed genetic KO and knockdown (KD) models of HSP90 isoforms (α and β) for extensive multi-omics-based in vitro and in vivo characterization and identified HSP90α as the primary driver of malignancy of the two isoforms in BCR-ABL1+ leukemia cells. Notably, combinatorial ex vivo drug sensitivity screenings identified CDK7 inhibitors (CDK7i) as drugs synergizing with HSP90α inhibition.
2024-01-26 | PXD041871 | Pride
Project description:lncRNA dependencies in acute myeloid leukemia
| PRJNA354371 | ENA
Project description:The importance of the stromal microenvironment in chronic lymphocytic leukemia (CLL) pathogenesis and drug resistance is well established. Despite recent advances in CLL therapy, identifying novel ways to disrupt interactions between CLL and its microenvironment may identify new combination partners for the drugs currently in use. To understand the role of microenvironmental factors on primary CLL cells, we took advantage of an observation that conditioned media (CM) collected from stroma was protective of CLL cells from spontaneous cell death ex vivo. The cytokine in the CM-dependent cells that most supports CLL survival in short term ex-vivo culture was CCL2. Pre-treatment of CLL cells with anti-CCL2 antibody enhanced venetoclax-mediated killing. Surprisingly, we found a group of CLL samples (9 of 23 cases) that are less likely to undergo cell death in the absence of CM support. Functional studies revealed that CM-independent (CMI) CLL cells are less sensitive to apoptosis than conventional stroma-dependent CLL. Additionally, a majority of the CMI CLL samples (80%) harbored unmutated IGHV. Bulk-RNA Seq analysis revealed upregulation of the focal adhesion and Ras signaling pathways in this group, along with expression of FLT3 and CD135 expression. Treatment with FLT3 inhibitors caused a significant reduction in cell viability among CMI samples. In summary, we were able to discriminate and target two biologically distinct subgroups of CLL based on CM dependence with distinct microenvironmental vulnerabilities.
2023-09-01 | GSE237907 | GEO
Project description:Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR-Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacological small-molecule inhibition of the menin-MLL protein interaction had profound anti-leukemic activity in human and murine models of NPM1mut AML in vitro and in vivo. Combined pharmacological inhibition of menin-MLL and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia. Together, MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1 and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on target activity and constitutes a novel therapeutic concept for this common AML subtype. RNA sequencing data of the human AML cell lines OCI-AML2 and OCI-AML3 comparing EPZ004777 [10µM] drug treatment versus DMSO vehicle control; experiments performed in biological triplicates.
2016-08-22 | E-GEOD-85107 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is a fatal disease characterized by a bleak prognosis. For over four decades, treatment options for AML have been constrained to administering high-dose cytotoxic chemotherapy. However, the emergence of drug resistance and the resultant toxic side effects have created an urgent necessity for identifying novel therapeutic targets. In this study, non-receptor protein tyrosine phosphatase type 2 (PTPN2) is highly expressed in AML. Remarkably, knock down of PTPN2 expression markedly mitigated AML burden both in vitro and in vivo. Additionally, we unveiled the direct interaction between PTPN2 and C-MYC, establishing C-MYC as a direct acting substrate of PTPN2. Then, we performed a small-molecule compound screening to identify K73, a selective inhibitor of PTPN2. At the same time, K73 showed a good safety profile and exhibited strong activity against AML in vivo. In conclusion, we have pinpointed a considerable therapeutic potential in targeting PTPN2 for AML treatment and discovered a novel class of selective PTPN2 inhibitors suitable for AML therapy.
2024-01-24 | PXD048854 | iProX
Project description:Leukemia cell proliferation requires up-regulation and rewiring of metabolic pathways to feed anabolic cell growth. Oncogenic drivers directly and indirectly regulate metabolic pathways, and aberrant metabolism is central not only for leukemia proliferation and survival, but also mediates oncogene addiction with significant implications for the development of targeted therapies. This review explores leukemia metabolic circuitries feeding anabolism, redox potential, and energy required for tumor propagation with an emphasis on emerging therapeutic opportunities.
| S-EPMC6824464 | biostudies-literature