Targeting PI3Kgamma dependency in leukemia treatment [ATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA1019355 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Targeting PI3Kgamma dependency in leukemia treatment [PI3Kgamma inhibition]
| PRJNA1019338 | ENA
Project description:Targeting PI3Kgamma dependency in leukemia treatment
| PRJNA1019359 | ENA
Project description:Targeting PI3Kgamma dependency in leukemia treatment [cytarabine persistence]
| PRJNA1019362 | ENA
Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
2024-03-18 | GSE243666 | GEO
Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
2024-03-18 | GSE243654 | GEO
Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
2024-03-18 | GSE243669 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-03-18 | GSE243670 | GEO
Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 kinase as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.
2024-03-19 | PXD045702 | Pride
Project description:Myeloid leukemia dependency MYNRL15 exemplifies class of CTCF-bound lncRNA loci [ATAC-Seq]
| PRJNA722506 | ENA
Project description:While therapies targeting CD19 by antibodies, CAR-T cells and T cell engagers have improved the response rates in B-cell malignancies; the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19-immunotoxin. Single-cell (sc) RNAseq showed increase in transcriptionally distinct CD19low populations in resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19low resistant cells. ATAC-seq showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B-ALL that relapsed after CD19 CAR-T targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19low resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both BTK and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.
2024-03-06 | GSE255305 | GEO