Summary of Study ST002446

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001577. The data can be accessed directly via it's Project DOI: 10.21228/M8VD8T This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002446
Study TitleUntargeted metabolomics of miR-142 WT vs KO CML cells
Study SummaryMiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.
Institute
Translational Genomics Research Institute
Last NameMansfield
First NameKrystine
Address445 N 5th St, Phoenix, AZ, 85004, USA
Emailkgarcia@tgen.org
Phone602-343-8832
Submit Date2023-01-13
Num Groups2
Total Subjects18
Num Males9
Num Females9
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2023-08-08
Release Version1
Krystine Mansfield Krystine Mansfield
https://dx.doi.org/10.21228/M8VD8T
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Combined analysis:

Analysis ID AN003984 AN003985 AN003986 AN003987
Analysis type MS MS MS MS
Chromatography type Reversed phase Reversed phase HILIC HILIC
Chromatography system Thermo Dionex Ultimate 3000 RS Thermo Dionex Ultimate 3000 RS Thermo Dionex Ultimate 3000 RS Thermo Dionex Ultimate 3000 RS
Column Thermo Hypersil GOLD C18 (150 x 2.1mm, 1.9um) Thermo Hypersil GOLD C18 (150 x 2.1mm, 1.9um) Waters ACQUITY UPLC BEH Amide (100 x 2.1mm,1.7um) Waters ACQUITY UPLC BEH Amide (100 x 2.1mm,1.7um)
MS Type ESI ESI ESI ESI
MS instrument type Orbitrap Orbitrap Orbitrap Orbitrap
MS instrument name Thermo Fusion Tribrid Orbitrap Thermo Fusion Tribrid Orbitrap Thermo Fusion Tribrid Orbitrap Thermo Fusion Tribrid Orbitrap
Ion Mode POSITIVE NEGATIVE POSITIVE NEGATIVE
Units Peak Area Peak Area Peak Area Peak area

Chromatography:

Chromatography ID:CH002946
Instrument Name:Thermo Dionex Ultimate 3000 RS
Column Name:Thermo Hypersil GOLD C18 (150 x 2.1mm, 1.9um)
Column Temperature:40
Flow Gradient:10 min linear gradient from 100% solvent A and 0% solvent B to 2% solvent A and 98% solvent B, and 5 min of equilibration time
Flow Rate:0.35 mL/min
Solvent A:100% water; 0.1% formic acid
Solvent B:100% acetonitrile; 0.1% formic acid
Chromatography Type:Reversed phase
  
Chromatography ID:CH002947
Instrument Name:Thermo Dionex Ultimate 3000 RS
Column Name:Waters ACQUITY UPLC BEH Amide (100 x 2.1mm,1.7um)
Column Temperature:40
Flow Gradient:99% B for 1 min, 99% to 85% for 2 min, 85% to 75% B for 3 min, 75% to 30% B for 3 min, 30% B for 1 min and 5 min column equilibration at 99% B
Flow Rate:0.4 mL/min
Solvent A:95% water/5% acetonitrile; 10 mM ammonium acetate
Solvent B:95% acetonitrile/5% water; 10 mM ammonium acetate
Chromatography Type:HILIC
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