|
| Status |
Public on Nov 28, 2023 |
| Title |
Modeling myelodysplastic syndromes in mice by altered Hoxa1 spliceform expression (CMP) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
The homeobox gene, Hoxa1, has two different isoforms generated by alternative splicing: a full-length homeodomain-containing Hoxa1 (Hoxa1-FL), and a truncated Hoxa1 (Hoxa1-T), that lacks the homeodomain. Oncoretroviral overexpression of wildtype Hoxa1 cDNA (WT-Hoxa1), which generates both Hoxa1 isoforms, in murine hematopoietic stem and progenitor cells (HSPCs) perturbed hematopoiesis, resulting in myelodysplastic syndromes (MDS) in mice. Overexpression of a mutated Hoxa1 cDNA (MUT-Hoxa1) that generates Hoxa1-FL but not Hoxa1-T led to a more severe MDS capable of transforming to secondary acute myeloid leukemia (sAML). Similar to human MDS, DNA damage repair pathways were downregulated in Hoxa1-overexpressing hematopoietic progenitor cells. Conditional knock-in mouse models revealed a Hoxa1-FL dosage-dependent effect on MDS disease severity. Our data reveal that increased expression of Hoxa1-FL in HSPCs is sufficient to initiate MDS in mice. CD34+ cells from up to 50% of patients with MDS had elevated HOXA1-FL expression, highlighting the clinical relevance of our mouse models.
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| |
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| Overall design |
Three vector groups (MXIE, WT-Hoxa1 and MUT-Hoxa1) were compared.
|
| Web link |
https://www.biorxiv.org/content/10.1101/2023.04.24.538176v1
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| |
|
| Contributor(s) |
Joseph C, Hendy J, Baker EK, Chalk AM, Gudas LJ, Fabb SA, Wall M, Walkley CR, Purton LE |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Mar 20, 2023 |
| Last update date |
Nov 29, 2023 |
| Contact name |
Alistair Morgan Chalk |
| E-mail(s) |
achalk@svi.edu.au, alistair.chalk@gmail.com
|
| Organization name |
St Vincent's Institute of Medical Research
|
| Department |
Stem Cell Regulation Unit
|
| Lab |
Walkley
|
| Street address |
9 Princes st, Fitzroy
|
| City |
Melbourne |
| State/province |
VIC |
| ZIP/Postal code |
3065 |
| Country |
Australia |
| |
|
| Platforms (1) |
| GPL11533 |
[MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version] |
|
| Samples (11)
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| Relations |
| BioProject |
PRJNA946799 |
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