Dysregulated expression of Hoxa1 isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes.

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. Statement of SignificanceOur study demonstrates that Hoxa1 is a key regulator of HSPCs and that increased expression of the transcriptionally active Hoxa1-FL can initiate MDS in mice. Furthermore, HOXA1-FL expression is upregulated in a significant proportion of human MDS patients and likely contributes to the disease in these patients.