Dysregulated expression ofHoxa1isoforms 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. The effects of the distinct Hoxa1 isoforms in hematopoiesis have not been investigated. Oncoretroviral studies revealed that Hoxa1-T acts in a dominant negative manner, regulating transcriptionally active Hoxa1. Oncoretroviral overexpression of wildtype Hoxa1 ( WT-Hoxa1 ), which generates both Hoxa1 isoforms, in murine hematopoietic stem and progenitor cells (HSPCs) perturbed hematopoiesis, resulting in transplantable 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 that transformed to secondary acute myeloid leukemia (sAML). DNA damage repair pathways were downregulated in Hoxa1 -overexpressing hematopoietic progenitor cells, accompanied by increased γH2AX foci. In silico analyses revealed that CD34+ cells from approximately 50% of patients with MDS had elevated HOXA1-FL expression. Conditional knock-in WT-Hoxa1 and MUT-Hoxa1 mice were generated and had features of pre-MDS, developing altered hematopoiesis within 4 months of Hoxa1 isoform overexpression in HSPCs. HSPCs were significantly reduced in all knock-in mice, accompanied by significantly increased apoptosis in WT-Hoxa1 HSPCs. Healthy wildtype recipients transplanted with bone marrow cells from Hoxa1 knock-in mice developed trilineage MDS, with Hoxa1 isoform and gene dosage dependent phenotypes. Collectively our data identify a role for HOXA1 in the pathogenesis of MDS. Our Hoxa1 mouse models capture different stages of progression of disease from pre-MDS to MDS to sAML and provide novel, clinically relevant tools to study MDS. Key points HOXA1 is upregulated in approximately 50% of MDS patient CD34+ BM cells, highlighting a potential role for HOXA1 in the pathogenesis of MDS. Dysregulated expression of Hoxa1 isoforms in murine hematopoietic stem and progenitor cells predisposes mice to pre-MDS and MDS.