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• W4310163439 abstract "Cytoplasmic dislocation and loss of the nucleolar localization of the chaperone protein NPM1 occurs in 30% of AML following a heterozygous frame shift C-terminal mutation in exon 11 of NPM1 (creating NPM1c), which contributes to differentiation arrest, growth, and self-renewal of AML stem progenitor cells. AML with mutant NPM1c express HOXA9 and its co-factor MEIS1, as well as their targets. This results in susceptibility of NPM1c-AML cells to Menin inhibitor (MI)-induced growth inhibition, differentiation and loss of viability. In present studies, utilizing mutant (mt) NPM1-targeted gRNAs (compared to control gRNA) and CRISPR-Cas9 editing, we determined the effect of mtNPM1 and NPM1c knockout on active enhancers (by ChIP-Seq with anti-H3K27Ac and H3K4Me3 antibodies), transcriptome (by RNA-Seq) and proteome (RPPA and Western analyses), as well as on cell growth and viability of OCI-AML3 cells. NPM1c KO markedly reduced the NPM1c levels, inhibited cell numbers growth (decrease in S phase and increase in G1 phase of the cell cycle), induced morphologic features of differentiation (increased % of myelocytes and metamyelocytes) in OCI-AML3 cells. ChIP-Seq analysis with H3K27Ac antibody following NPM1c KO demonstrated reduced H3K27Ac peak density at the super-enhancers of MYC, MEIS1, and HOXA9. RNA-Seq analysis showed negative enrichment of HALLMARK or TFT (transcription factor target) mRNAs gene-sets, including those of MEIS1/HOXA9 and MYC targets, and gene-sets of ribosome/translation and cell cycle. QPCR analyses showed significant depletion of mRNA levels of HOXA9, MEIS1, PBX3 and c-Myc, while inducing ITGAM and p21 mRNA levels (p < 0.05). This was associated with depletion of protein levels of NPM1c, c-Myc, and MEIS1, but upregulation of PU.1, RUNX1, CD11b, and p21 protein levels. Compared to control OCI-AML3, OCI-AML3 with NPM1 KO exhibited abrogation of the Menin inhibitor SNDX-50469-induced apoptosis. Additionally, compared to control cells, NPM1c KO significantly reduced sensitivity of OCI-AML3 cells to apoptosis induced by targeted agents previously shown to demonstrate efficacy against AML cells with NPM1c, including KPT-330 (XPO1 inhibitor), homoharringtonine (protein translation inhibitor), and anti-AML chemotherapeutic agents, including daunorubicin, cytarabine and etoposide. However, NPM1c KO sensitized OCI-AML3 cells to ATRA (all trans retinoic acid)-induced differentiation, which was associated with marked induction of p21 and CD11b. Utilizing the RNA-Seq signature of NPM1c KO and interrogating the LINCS1000-CMap data set of gene expression signatures, we determined that among the top expression mimickers were several pan-HDAC inhibitors and a WEE1 kinase inhibitor. Consistent with this, in vitro treatment with adavosertib (WEE1 inhibitor, MK-1775) or panobinostat (HDAC inhibitor) dose-dependently induced apoptosis in OCI-AML3 cells, as well as in 5 samples of patient-derived (PD) AML cells with mtNPM1 that were relatively resistant to SNDX-50469. In a PDX model of tail-vein transfused, luciferase-transduced AML cells, treatment with panobinostat (5 mg/kg/T.I.W., IP) or adavosertib (60 mg/kg, orally) significantly reduced the AML burden and improved the median and overall survival of the NSG mice (p < 0.005), without inducing significant toxicity. Notably, in vitro co-treatment of adavosertib or panobinostat with SNDX50469 synergistically induced lethality in OCI-AML3 and PD AML cells with mtNPM1. Additionally, co-treatment with panobinostat and adavosertib was synergistically lethal in OCI-AML3 as well as PD AML cells with mtNPM1. Taken together, these findings highlight that the expression of NPM1c mechanistically regulates the sensitivity of AML cells to Menin inhibitor, XPO inhibitor, anti-AML chemotherapeutic agents, as well as ATRA-induced differentiation. Our findings also identify the non-chemotherapy agents pan-HDAC inhibitor and WEE1 inhibitor for further development with Menin inhibitor against AML with NPM1c." @default.
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• W4310163439 date "2022-11-15" @default.
• W4310163439 modified "2023-09-30" @default.
• W4310163439 title "Efficacy of Novel Non-Chemotherapy Combinations Against AML Cells with Mutant NPM1" @default.
• W4310163439 doi "https://doi.org/10.1182/blood-2022-169584" @default.
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