Gene expression alteration regulated by BCAA-metabolism in human acute leukemia
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ABSTRACT:
PROVIDER: PRJNA545241 | ENA |
REPOSITORIES: ENA
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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.
2019-08-01 | GSE132512 | GEO
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. 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.
2019-07-01 | GSE131815 | GEO
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. 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.
2019-07-01 | GSE131814 | GEO
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. 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.
2019-07-01 | GSE131813 | GEO
Project description:Acute myeloid leukemia (AML) harboring DNMT3A mutation exhibits epigenetic dysregulation, chemoresistance and poor outcome, but the underlining mechanism remains elusive. Here, inspired by the unexpected finding that DNMT3A-mutated AML patients exhibit a unique translatome landscape, we connected this epigenetic mutation to translational dysregulation through reprogrammed branched-chain amino acid (BCAA) metabolism. Particularly, DNMT3A mutation induces DNA hypomethylation-dependent activation of BCAT1, a rate-limiting aminotransferase gene for BCAA metabolism. Thereafter, the accumulation of intracellular BCAA more profoundly alters translation of a select subset of transcripts with higher BCAA codon ratios. Accordingly, deficiency in BCAA availability reduces the translation of target genes and attenuated the proliferative advantages of DNMT3A-mutated AML cells. More importantly, the pharmacological inhibition of BCAT1 with Gabapentin normalized BCAA levels, reversed target genes translation and repressed leukemia cell growth specifically in DNMT3A-mutated AML cells. Collectively, these findings uncovered a novel epigenetics-metabolism axis, in which DNMT3A mutation boosts BCAA metabolism thereby not only forming a positive feedback loop to enhance DNA hypomethylation through alpha ketoglutarate (α-KG)-dependent ten-eleven translocation (TET) activation, but also affecting gene translation in a BCAA codon-biased manner. Moreover, the efficacy of Gabapentin in suppressing AML cell proliferation highlights the clinical relevance of targeting BCAA metabolism to improve outcomes of DNMT3A-mutated AML.
2026-05-31 | GSE296332 | GEO
Project description:Acute myeloid leukemia (AML) harboring DNMT3A mutation exhibits epigenetic dysregulation, chemoresistance and poor outcome, but the underlining mechanism remains elusive. Here, inspired by the unexpected finding that DNMT3A-mutated AML patients exhibit a unique translatome landscape, we connected this epigenetic mutation to translational dysregulation through reprogrammed branched-chain amino acid (BCAA) metabolism. Particularly, DNMT3A mutation induces DNA hypomethylation-dependent activation of BCAT1, a rate-limiting aminotransferase gene for BCAA metabolism. Thereafter, the accumulation of intracellular BCAA more profoundly alters translation of a select subset of transcripts with higher BCAA codon ratios. Accordingly, deficiency in BCAA availability reduces the translation of target genes and attenuated the proliferative advantages of DNMT3A-mutated AML cells. More importantly, the pharmacological inhibition of BCAT1 with Gabapentin normalized BCAA levels, reversed target genes translation and repressed leukemia cell growth specifically in DNMT3A-mutated AML cells. Collectively, these findings uncovered a novel epigenetics-metabolism axis, in which DNMT3A mutation boosts BCAA metabolism thereby not only forming a positive feedback loop to enhance DNA hypomethylation through alpha ketoglutarate (α-KG)-dependent ten-eleven translocation (TET) activation, but also affecting gene translation in a BCAA codon-biased manner. Moreover, the efficacy of Gabapentin in suppressing AML cell proliferation highlights the clinical relevance of targeting BCAA metabolism to improve outcomes of DNMT3A-mutated AML.
2026-05-31 | GSE296563 | GEO
Project description:METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism
| PRJNA785622 | ENA
Project description:Genome-wide maps of H3K27me3 chromatin modification status regulated by branched chain amino acids (BCAA) metabolism in human acute leukemia
| PRJNA548258 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-07-01 | GSE131888 | GEO
Project description:We used RNA-Seq to ask whether the transcripts for the proposed BCKDH subunits are upregulated in wild-type plants subjected to prolonged darkness. These experiments were performed using rosette leaves from 5-week-old, short-day-grown (8h light/16h dark) Col-0 wild-type plants moved to constant darkness for 6h, 24h, 48h and 72h, and grown in short day for 72h as control. The transcripts of eight BCAA catabolism genes were increased nine- to 400-fold within the first 6h of prolonged darkness, and remained high until the last time point. These results are consistent with the hypothesis that BCAA catabolic enzymes - including BCKDH subunits E1A1, E1B1, E1B2 and E2 - have one or more physiological roles in the dark. Rosette leaf mRNA profiles of 5-week old Col wild type (WT, CS60000) and BCAA catabolic mutants ivd1-2 and hml1-2 were generated byRNA sequencing, in duplicate, using Illumina HiSeq2500.
2015-04-16 | E-GEOD-67956 | biostudies-arrayexpress