Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA90081 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Gene expression profiling in BCR/ABL expressing LSCs and BCR/ABL expressing Alox5-/-LSCs
| PRJNA138603 | ENA
Project description:Gene expression profiling in BCR-ABL expressing LSCs and BCR-ABL-BLK expressing LSCs
| PRJNA151801 | ENA
Project description:Gene expression profiling in BCR/ABL-expressing LSCs and BCR/ABL-expressing Hif1a-/-LSCs
| PRJNA156155 | ENA
Project description:Gene expression profiling in BCR/ABL expressing HSCs
| PRJNA107207 | ENA
Project description: Not available
| S-EPMC8784167 | biostudies-literature
Project description:BCR-ABL-mediated recruitment of STAT5 revealed by ChIPseq
| PRJNA399109 | ENA
Project description:Expression profile of BCR-ABL+ colonies, isolated from methylcellulose
| PRJNA344728 | ENA
Project description:Expression profile of Imatinib treated BAF3 -BCR-ABL cells
| PRJNA302300 | ENA
Project description:MiR-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.
2023-01-13 | ST002446 | MetabolomicsWorkbench
Project description:The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome positive acute lymphatic leukemia
| PRJNA246571 | ENA