Dysregulated expression ofHoxa1isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes

Abstract

AbstractThe homeobox gene,Hoxa1, has two different isoforms generated by alternative splicing: a full-length homeodomain-containingHoxa1(Hoxa1-FL), and a truncatedHoxa1(Hoxa1-T), that lacks the homeodomain. Oncoretroviral overexpression of wildtypeHoxa1cDNA (WT-Hoxa1), which generates bothHoxa1isoforms, in murine hematopoietic stem and progenitor cells (HSPCs) perturbed hematopoiesis, resulting in myelodysplastic syndromes (MDS) in mice. Overexpression of a mutatedHoxa1cDNA (MUT-Hoxa1) that generatesHoxa1-FLbut notHoxa1-Tled to a more severe MDS capable of transforming to secondary acute myeloid leukemia (sAML). Similar to human MDS, DNA damage repair pathways were downregulated inHoxa1-overexpressing hematopoietic progenitor cells. Conditional knock-in mouse models revealed aHoxa1-FLdosage-dependent effect on MDS disease severity. Our data reveal that increased expression ofHoxa1-FLin HSPCs is sufficient to initiate MDS in mice. CD34+ cells from up to 50% of patients with MDS had elevatedHOXA1-FLexpression, highlighting the clinical relevance of our mouse models.Statement of SignificanceOur study demonstrates thatHoxa1is a key regulator of HSPCs and that increased expression of the transcriptionally activeHoxa1-FLcan initiate MDS in mice. Furthermore,HOXA1-FLexpression is upregulated in a significant proportion of human MDS patients and likely contributes to the disease in these patients.