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Gene expression analysis of Jurkat cells cultured with or without BCAA

ABSTRACT: The branched-chain amino acid (BCAA) metabolism plays pleiotropic roles in homeostasis. Here we show that human acute leukemia-initiating cells (LICs), but not normal hematopoietic stem cells, are heavily addicted to the BCAA metabolism, irrespective of myeloid or lymphoid types. To clarify how BCAA metabolism affect the gene expression of human acute leukemia cells, we examined the gene expression alteration in human acute leukemia cell lines in control and BCAA-resrticted culture conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131815 | GEO | 2019/07/01

REPOSITORIES: GEO

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Genome-wide maps of H3K27me3 chromatin modification status regulated by branched chain amino acids (BCAA) metabolism in human acute leukemia

Project description:The branched-chain amino acid (BCAA) metabolism plays pleiotropic roles in homeostasis. Here we show that human acute leukemia-initiating cells (LICs), but not normal hematopoietic stem cells, are heavily addicted to the BCAA metabolism, irrespective of myeloid or lymphoid types. Human acute leukemia cells had a high level of BCAAs, transporting free BCAAs into the cytoplasm. Functional inhibition of BCAA transaminase-1 (BCAT1), a catalytic enzyme for BCAAs, induced apoptosis of human LICs, and suppressed reconstitution of human leukemia in xenograft models. Furthermore, deprivation of BCAAs from daily diet in mice transplanted with human LICs strongly inhibited their expansion and self-renewal in vivo. The BCAT1 inhibition inactivates the PRC2 function for epigenetic maintenance of stem cell signatures via downregulation of EZH2 and EED, critical PRC2 components, and inhibited the mTORC1 signaling for leukemia propagation. Thus, targeting the BCAA metabolism should be a powerful approach to erase cancer stemness in human acute leukemias.

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Gene expression alteration regulated by BCAA-metabolism in human acute leukemia

Project description:Gene expression alteration regulated by BCAA-metabolism in human acute leukemia

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Whole exome sequencing analysis of bone marrow c-Kit+ leukemia cells in Nras-G12D with Ezh2 KO (E2-KO) mice

Project description:Epigenetic gene regulation and metabolism are highly intertwined, yet little is known whether and how altered epigenetics influences cellular metabolism in cancer progression. Here we show that EZH2 and NRasG12D mutations cooperatively induce progression of myeloproliferative neoplasms to fully penetrant, transplantable and lethal myeloid leukemias in mouse. EZH1, an EZH2 homolog, is indispensable for EZH2-deficient leukemia-initiating cells (LICs) and constitutes an epigenetic vulnerability. BCAT1, the first enzyme catalyzing transamination of branched-chain amino acids (BCAAs), is repressed by EZH2 in normal hematopoiesis and aberrantly activated in EZH2-deficient myeloid neoplasms in mouse and human. Enhanced BCAT1 promotes BCAA production in LICs ex vivo and in vivo, resulting in activated mTOR signaling. Genetic and pharmacological inhibition of BCAT1 selectively impairs EZH2-deficient LICs and constitutes a metabolic vulnerability. These findings establish an example how epigenetic alterations modify metabolic adaptation in myeloid transformation and provide a rationale for targeting the epigenetic and metabolic liabilities of cancer-initiating cells.

2019-09-01 | GSE122585 | GEO

RNA-seq analysis of transcriptomic changes in bone marrow LSK cells in WT, G12D, Ezh2-KO and G12D with Ezh2-KO (G12D_Ezh2-KO) mice [RNA-seq]

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ChIP-seq analysis of H3K4me3,H3K27ac and H3K27me3 in bone marrow LSK cells in WT, G12D, Ezh2-KO and G12D with Ezh2-KO (G12D_Ezh2-KO) mice

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The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase

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2018-05-18 | PXD009122 | Pride

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