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| Status |
Public on May 29, 2024 |
| Title |
Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML (WES) |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies like MDS and AML. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in MDS and AML, cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO HSPCs expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.
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| Overall design |
Genomic DNA isolated from FACS sorted BM GFP+/lin-/ckit+/Sca+ cells from WT/vector (n=3), WT/RUNX1mut (n=3), miR-146aKO/vector (n = 3), and miR-146aKO/RUNX1mut secondary transplanted mice were submitted to Otogenetics Corporation (Atlanta, GA, USA) for mouse exome capture and sequencing
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| Contributor(s) |
Barreyro L, Choi K, Starczynowski DT |
| Citation(s) |
38784013 |
| |
| Submission date |
Apr 15, 2024 |
| Last update date |
May 30, 2024 |
| Contact name |
Kwangmin Choi |
| Organization name |
Cincinnati Children's Hospital Medical Center
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| Department |
Experimental Hematology & Cancer Biology
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| Street address |
333 Burnet Avenue
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| City |
Cincinnati |
| State/province |
Ohio |
| ZIP/Postal code |
45229 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE264053 |
Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML |
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| Relations |
| BioProject |
PRJNA1100617 |
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