Oncotarget

Research Papers:

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

Cristina Prieto, Rolf Marschalek, Alessa Kühn, Adelheid Bursen, Clara Bueno and Pablo Menéndez _

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Oncotarget. 2017; 8:81936-81941. https://doi.org/10.18632/oncotarget.19567

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Abstract

Cristina Prieto1, Rolf Marschalek2, Alessa Kühn2, Adelheid Bursen2, Clara Bueno1,3 and Pablo Menéndez1,3,4

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 Investigación Biomédica en Red de Cancer (CIBERONC), Barcelona, Spain

4 Instituciò Catalana de Recerca i Estudis Avançats, Barcelona, Spain

Correspondence to:

Pablo Menéndez, 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.


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