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CC BY-NC-ND V4.0, Open Access
Preprint
Dysregulated expression of Hoxa1isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes
bioRxiv
Cold Spring Habor Laboratory
2023
Abstract
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.
Details
- Title
- Dysregulated expression of Hoxa1isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes
- Authors/Creators
- ShuhYing TanChacko JosephAlistair M ChalkJean HendyStewart FabbKelli SchleibsSamuel C LeeGavin TjinClea S GraceVinodini MadugalleMonique F SmeetsAna C MaluendaKim L RiceEmma K BakerHarshal NandurkarChristopher I SlapeMichael W ParkerAshwin UnnikrishnanGhulam J MuftiMagnus TobiassonEva Hellstrom-LindbergJohn E PimandaLorraine J GudasJessica K HolienCarl R WalkleyMeaghan WallLouise E Purton
- Publication Details
- bioRxiv
- Publisher
- Cold Spring Habor Laboratory
- Identifiers
- 991005635770107891
- Copyright
- The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Preprint
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