Modeling myelodysplastic syndromes in mice by altered Hoxa1 spliceform expression

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. 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