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| Status |
Public on Nov 28, 2023 |
| Title |
Modeling myelodysplastic syndromes in mice by altered Hoxa1 spliceform expression |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| 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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| Overall design |
5000-78,000 sorted (MEP) cells with overexpression of Wild type Hoxa1 (WT- Hoxa1), Mutant Hoxa1 (MUT-Hoxa1) or control vector (MXIE) from primary recipient mice 16 weeks post transplantation.
Three vector groups (MXIE, WT-Hoxa1 and MUT-Hoxa1) were compared.
Joseph C: St. Vincent’s Institute, Melbourne, Australia
Hendy J: St. Vincent’s Institute, Melbourne, Australia
Baker EK: St. Vincent’s Institute, Melbourne, Australia
Chalk AM: Stem Cell Regulation Unit, St. Vincent’s Institute, Melbourne, Australia
Gudas LJ: Department of Pharmacology, Weill Cornell Medical College, New York, NY
Fabb SA: Monash University, Carlton, Australia
Wall M: Victorian Cancer Cytogenetics Service, St. Vincent’s Hospital, Melbourne, Australia
Walkley CR: St. Vincent’s Institute, Melbourne, Australia
Purton LE: St. Vincent’s Institute, Melbourne, Australia
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| 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. |
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| Submission date |
Oct 30, 2014 |
| Last update date |
Nov 29, 2023 |
| Contact name |
Alistair Morgan Chalk |
| E-mail(s) |
achalk@svi.edu.au, alistair.chalk@gmail.com
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| Organization name |
St Vincent's Institute of Medical Research
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| Department |
Stem Cell Regulation Unit
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| Lab |
Walkley
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| Street address |
9 Princes st, Fitzroy
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| City |
Melbourne |
| State/province |
VIC |
| ZIP/Postal code |
3065 |
| Country |
Australia |
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| Platforms (1) |
| GPL11533 |
[MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version] |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA265844 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE62853_RAW.tar |
42.9 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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