The AF4-MLL fusion transiently augments multilineage hematopoietic engraftment but is not sufficient to initiate leukemia in cord blood CD34 + cells

// Cristina Prieto 1 , Rolf Marschalek 2 , Alessa Kuhn 2 , Adelheid Bursen 2 , Clara Bueno 1,3 and Pablo Menendez 1,3,4 1 Department of Biomedicine, Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Barcelona, Spain 2 Institute of Pharmaceutical Biology/DCAL, Goethe-University, Frankfurt, Germany 3 Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Barcelona, Spain 4 Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain Correspondence to: Pablo Menendez, email: // Clara Bueno, email: // Keywords : AF4-MLL, CD34 HSPCs, B cell acute lymphoblastic leukemia, leukemogenesis Received : April 19, 2017 Accepted : April 22, 2017 Published : July 26, 2017 Abstract The translocation t(4;11)(q21;q23) is the hallmark genetic abnormality associated with infant pro-B acute lymphoblastic leukemia (B-ALL) and has the highest frequency of rearrangement in Mixed-lineage leukemia (MLL) leukemias. Unlike other MLL translocations, MLL-AF4-induced proB-ALL is exceptionally difficult to model in mice/humans. Previous work has investigated the relevance of the reciprocal translocation fusion protein AF4-MLL for t(4;11) leukemia, finding that AF4-MLL is capable of inducing proB-ALL without requirement for MLL-AF4 when expressed in murine hematopoietic stem/progenitor cells (HSPCs). Therefore, AF4-MLL might represent a key genetic lesion contributing to t(4;11)-driven leukemogenesis. Here, we aimed to establish a humanized mouse model by using AF4-MLL to analyze its transformation potential in human cord blood-derived CD34 + HSPCs. We show that AF4-MLL-expressing human CD34 + HSPCs provide enhanced long-term hematopoietic reconstitution in primary immunodeficient recipients but are not endowed with subsequent self-renewal ability upon serial transplantation. Importantly, expression of AF4-MLL in primary neonatal CD34 + HSPCs failed to render any phenotypic or hematological sign of disease, and was therefore not sufficient to initiate leukemia within a 36-week follow-up. Species-specific (epi)-genetic intrinsic determinants may underlie the different outcome observed when AF4-MLL is expressed in murine or human HSPCs.