Project description:microRNA (miRNA or miR) are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify miR-196b, is overexpressed in high-risk subset of DNMT3A-mutant AML and its activity is important to maintain a differentiation block and limit innate immune signaling pathways in AML. We interrogated previously published experimentally defined and computationally predicated miR-196b targets demonstrating that miR-196b regulates Toll-like Receptor Signaling. This work uncovered that miR-196b represses TLR7/8 activation and innate immune signaling in AML and that TLR7/8 activates a Stat1 transcriptional response associated with induced co-stimulatory molecule expression on the surface of AML-derived monocytes and dendritic-like cells.
Project description:microRNA (miRNA or miR) are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify miR-196b, is overexpressed in high-risk subset of DNMT3A-mutant AML and its activity is important to maintain a differentiation block and limit innate immune signaling pathways in AML. We interrogated previously published experimentally defined and computationally predicated miR-196b targets demonstrating that miR-196b regulates Toll-like Receptor Signaling. This work uncovered that miR-196b represses TLR7/8 activation and innate immune signaling in AML and that TLR7/8 activates a Stat1 transcriptional response associated with induced co-stimulatory molecule expression on the surface of AML-derived monocytes and dendritic-like cells.
Project description:microRNA (miRNA or miR) are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify miR-196b, is overexpressed in high-risk subset of DNMT3A-mutant AML and its activity is important to maintain a differentiation block and limit innate immune signaling pathways in AML. We interrogated previously published experimentally defined and computationally predicated miR-196b targets demonstrating that miR-196b regulates Toll-like Receptor Signaling. This work uncovered that miR-196b represses TLR7/8 activation and innate immune signaling in AML and that TLR7/8 activates a Stat1 transcriptional response associated with induced co-stimulatory molecule expression on the surface of AML-derived monocytes and dendritic-like cells.
Project description:Acute myeloid leukemia (AML) is a fatal hematological malignancy for most patients, and DNA methyltransferase 3A (DNMT3A) mutations occur in about 30-35% of AML patients. We show graphdiyne oxide (GDYO), a member of two-dimensional carbon nanomaterials3, demonstrates an anti-leukemia effect in vitro and in vivo against AML cells with DNMT3A mutation specifically. Here, we used RNA-seq to depict transcriptome of AML cells with or without GDYO treatment.
Project description:To understand the pathogenesis of DNMT3A in acute monocytic leukemia (AML-M5), we identified genes that are expressed differently in leukemia cells from AML-M5 patients collected at diagnosis with DNMT3A mutations (6 cases) compared to those without the mutations (4 cases). Differences of expression level were observed in 889 out of 20,723 (4.3%) annotated genes by using Affymetrix microarray with 469 genes upregulated and 420 genes downregulated. Leukemia cells in bone marrow of acute monocytic leukemia patients were collected at diagnosis for RNA extraction and hybridization on Affymetrix microarrays. 6 cases of AML-M5 samples with DNMT3A mutations and 4 cases of AML-M5 samples wihtout DNMT3A mutations were used.
Project description:Acute myeloid leukemia (AML) is a fatal hematological malignancy for most patients, and DNA methyltransferase 3A (DNMT3A) mutations occur in about 30-35% of AML patients. We show graphdiyne oxide (GDYO), a member of two-dimensional carbon nanomaterials3, demonstrates an anti-leukemia effect in vitro and in vivo against AML cells with DNMT3A mutation specifically. Here, we used reduced representation bisulfite sequencing (RRBS) to depict DNA methylome of AML cells with or without GDYO treatment.
Project description:DNA methyltransferase 3A (DNMT3A) gene is mutated in various myeloid neoplasms including acute myeloid leukemia (AML), especially at the Arg882 and associated with inferior outcomes. Despite the current progress of functional role of DNMT3A mutations, the molecular pathogenesis of myeloid malignancies remains poorly understood. The mechanisms of AML transformation and functional role of DNMT3A mutations through its target genes in the leukemogenesis remain to be explored. Here we wished to perform the differential gene expression profile in U937 cells over-expressed with DNMT3A-Arg882His/Cys (R882H/C) mutations including DNMT3A-WT and vector. Results: Gene expression profiling analysis revealed aberrant expression of several cell-cycle and apoptosis-related genes in U937 cells transduced with mutant DNMT3A compared to WT- or vector control.
Project description:Adult de novo acute myeloid leukemia (AML) is a hematologic malignancy with poor prognosis, commonly driven by mutations in genes including the DNA methyltransferase DNMT3A and nucleophosmin NPM1. We previously generated sequentially inducible mouse models of these mutations and observed transformation from clonal hematopoiesis (CH) to myeloproliferative disorder to AML. In transformed AML, leukemia-propagating cells have a myeloid-restricted progenitor cell phenotype (c-Kit+). Here, to identify mechanisms that sustain tumorigenesis, we performed single-cell RNA-seq of c-Kit+ cells from four primary Dnmt3a;Npm1-mutant AML samples. The most primitive subset of c-Kit+ cells, a multipotent progenitor population Multi-Lin-2, had increased expression of the antioxidant and heavy metal chelator metallothionein 1 (Mt1) in all AML samples. Cas9-mediated Mt1 knockout in primary Dnmt3a;Npm1-mutant AML resulted in reduced cell cycling and proliferation and increased pyroptosis in vitro and increased overall survival following transplant into congenic recipient mice.