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| Status |
Public on Sep 01, 2019 |
| Title |
Whole exome sequencing analysis of bone marrow c-Kit+ leukemia cells in Nras-G12D with Ezh2 KO (E2-KO) mice |
| Organism |
Mus musculus |
| Experiment type |
Genome variation 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 |
Genome DNA were isolated from c-Kit+ leukemia cells from E2-KO moribund mice and processed for whole exome sequencing (WES) analysis using Agilent SureSelect XT Mouse All Exon Kit (cat# 1000001746) following manufacturer’s protocols. WES libraries were sequenced on BGISEQ500 platform by pair-end 100bp.
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| Contributor(s) |
Gu Z, Liu Y, Zhang Y, Xu J |
| Citation missing |
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| Submission date |
Nov 15, 2018 |
| Last update date |
Sep 03, 2019 |
| Contact name |
Jian Xu |
| E-mail(s) |
[email protected]
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| Phone |
9015955208
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| Organization name |
St. Jude Children's Research Hospital
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| Department |
Pathology
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| Street address |
262 Danny Thomas Place, MS 345
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| City |
Memphis |
| State/province |
Tennessee |
| ZIP/Postal code |
38105 |
| Country |
USA |
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| Platforms (1) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA505671 |
| SRA |
SRP168764 |
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