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| Status |
Public on Jun 17, 2019 |
| Title |
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] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
RNA-seq was performed to determine the transcriptomic changes in FACS-sorted LSK cells from WT, G12D, Ezh2-KO and G12D with Ezh2-KO (G12D_Ezh2-KO) mice
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| Contributor(s) |
Gu Z, Liu Y, Xu J |
| Citation(s) |
31189531, 34732703 |
| |
| Submission date |
Jun 03, 2019 |
| Last update date |
Nov 30, 2021 |
| Contact name |
Jian Xu |
| E-mail(s) |
Jian.Xu@stjude.org
|
| Phone |
9015955208
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| Organization name |
St. Jude Children's Research Hospital
|
| Department |
Pathology
|
| Street address |
262 Danny Thomas Place, MS 345
|
| City |
Memphis |
| State/province |
Tennessee |
| ZIP/Postal code |
38105 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (14)
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| This SubSeries is part of SuperSeries: |
| GSE112995 |
Epigenomic and transcriptomic analysis of bone marrow LSK cells in WT, G12D, Ezh2-KO, and G12D with Ezh2-KO mice |
|
| Relations |
| BioProject |
PRJNA545888 |
| SRA |
SRP200149 |
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