Dysregulated expression of Hoxa1 isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes
Year: 2023
Type: preprint
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. 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.
Authors: ShuhYing Tan, Chacko Joseph, Mohamed Luban Sobah, Alistair M. Chalk, Kelli Schleibs, Samuel C. Lee, Gavin Tjin, Sagrika Chugh, Xiaodong Mo, Clea S. Grace, Jia Q Truong, Monique F. Smeets, Kim L. Rice, Michael W Parker, Ashwin Unnikrishnan, Austin G. Kulasekararaj, Ghulam J. Mufti, Magnus Tobiasson, Eva Hellstrom-Lindberg, John E. Pimanda, Lorraine J. Gudas, Davis J. McCarthy, Jessica K. Holien, Carl R. Walkley, Meaghan Wall, Louise E. Purton
Institutions: The University of Melbourne, Australian Cancer Research Foundation, St Vincent's Hospital Melbourne, St Vincents Institute of Medical Research, Monash University, RMIT University, Centre National de la Recherche Scientifique, Inserm, Murdoch University, Génomes, biologie cellulaire et thérapeutiques, Sorbonne Paris Cité, La Ligue Contre le Cancer, Hôpital Saint-Louis, Université Paris Diderot, Institut Universitaire d'Hématologie, UNSW Sydney, Translational Research Institute, The University of Queensland, King's College Hospital, Karolinska University Hospital, Karolinska Institutet, Prince of Wales Hospital, Weill Cornell Medicine
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4366988272