Mouse models of MLL leukemia: recapitulating the human disease.
Chromosome translocations involving the mixed lineage leukemia (MLL) gene fuse it in frame with multiple partner genes creating novel fusion proteins (MLL-FPs) that cause aggressive acute leukemias in humans. Animal models of human disease are important for the exploration of underlying disease mechanisms as well as for testing novel therapeutic approaches. Patients carrying MLL-FPs have very few cooperating mutations, making MLL-FP driven leukemias ideal for animal modeling. The fact that the MLL-FP is the main driver mutation has allowed for a wide range of different experimental model systems designed to explore different aspects of MLL-FP leukemogenesis. In addition, MLL-FP driven acute myeloid leukemia (AML) in mice is often used as a general model for AML. This review provides an overview of different MLL-FP mouse model systems and discusses how well they have recapitulated aspects of the human disease as well as highlights the biological insights each model has provided into MLL-FP leukemogenesis. Many promising new drugs fail in the early stages of clinical trials. Lessons learned from past and present MLL-FP models may serve as a paradigm for designing more flexible and dynamic preclinical models for these as well as other acute leukemias.
Weatherall Institute of Molecular Medicine, Medical Research Council Molecular Haematology Unit, University of Oxford, Oxford, United Kingdom.
Thomas A
0000-0002-0413-4271
TA
Milne
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D013045:Species Specificity; D035602:Transcriptional Elongation Factors / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C090862:ELL protein, human; C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse