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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jun 25, 2020 |
| Title |
Sustained fetal hematopoiesis causes juvenile death from leukemia: evidence from a dual-age-specific mouse model |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
It is not clear whether disrupted age-specific hematopoiesis contributes to the complex manifestations in leukemia patients who carry identical mutations, particularly in pediatric and adult patients with similar clinical characteristics. By studying a dual-age-specific mouse model, we demonstrate: 1) loss of Pten during the fetal-to-adult hematopoiesis switch (HSC switch) causes sustained fetal hematopoiesis, resulting in death in juvenile leukemia; 2) myeloid-biased hematopoiesis in juvenile mice is associated with the sustained fetal properties of hematopoietic stem cells (HSCs); 3) the age specificity of juvenile myelomonocytic leukemia (JMML) depends on the dosage of Pten and Nf1; 4) single-allelic Pten deletion during the HSC switch causes constitutive activation of mitogen-activated protein kinase (MAPK) in juvenile mice with Nf1 loss of heterozygosity (LOH); and 5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that one copy of Pten is sufficient to maintain an intact negative feedback loop of the Akt pathway and HSC function in reconstitution, despite MAPK being constitutively activated in juvenile mice with Pten+/DNf1LOH. However, two copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. Our data indicate that previous investigations of Pten function in wild type mice may not reflect the impact of Pten loss in mice with Nf1 mutations or other genetic defects. We provide a proof-of-concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise.
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| Overall design |
Case (JMML) vs. control (WT) experiment. 3 replicates in each group.
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| Contributor(s) |
Vara N, Liu Y, Yan Y, Lensing SY, Colorado N, Robinson D, Zhang J, Zhang X, Peterson EA, Baltz NJ, Zhou D, Bertaina A, Johann DJ Jr, Emanuel PD, Liu YL |
| Citation(s) |
32777070 |
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| Submission date |
Sep 09, 2019 |
| Last update date |
Aug 24, 2020 |
| Contact name |
Y. Lucy Liu |
| E-mail(s) |
ylliu19@stanford.edu
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| Organization name |
Stanford Medical School
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| Department |
Pediatrics
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| Street address |
240 Pasteur Drive, BMI Suite 2550
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| City |
Stanford |
| State/province |
CA |
| ZIP/Postal code |
94305-5139 |
| Country |
USA |
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| Platforms (1) |
| GPL21493 |
Illumina HiSeq 3000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA564652 |
| SRA |
SRP221161 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE137152_RAW.tar |
1.0 Mb |
(http)(custom) |
TAR (of TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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