GEMMs addressing Pax5 loss-of-function in childhood pB-ALL

Germline mutations in transcription factors, which are implicated in hematopoiesis in general or specifically in B-cell differentiation have recently been described to confer an inherited risk to pB-ALL with often reduced penetrance. Predicting leukemia development, therapy response and long term follow up of mutation carriers is challenging because experience from large patient cohorts and their long term follow up are not available.Genetically Engineered Murine Models (GEMMs) represent a promising approach to create individualized and precise models reproducing the molecular makeup of the human disease. This review focuses on PAX5 loss-of-function and summarizes techniques of murine model generation, available GEMMs, which mimic Pax5 loss-of-function in leukemia development and discusses the challenges and drawbacks of these models. These aspects are discussed in the context of creating a robust model, which serves not only for validation of the relevance of a genomic alteration in pB-ALL but at the same time as a valid preclinical model.J.H. has been supported by the German Children’s Cancer Foundation (110997) and from the “Forschungskommission” of the medical faculty of the Heinrich Heine University and the “Strategischer Forschungsfond” of the Heinrich-Heine-University. A.B. has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. A.B. has been supported by the German Carreras Foundation (DJCLS R13/26). Research in ISG group is partially supported by FEDER and by MINECO (SAF2012-32810, and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), National Institutes of Health grant (R01 CA109335-04A1), Junta de Castilla y León (BIO/SA32/14, BIO/SA51/15 and CSI001U14), and the Fundacion Inocente Inocente. Research at CC's lab is partially supported by FEDER, ISCIII (PI13/00160 and PI14/00025) and Fundación Inocente Inocente.Peer Reviewe