MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment

• Published in: Oncogene Vol. 36; no. 22; pp. 3207 - 3212
• Main Authors: Ugale, A, Säwén, P, Dudenhöffer-Pfeifer, M, Wahlestedt, M, Norddahl, G L, Bryder, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2017; Nature Publishing Group
• Subjects: 13; 13/31; 631/67/1990; 631/67/1990/283; 64; 64/60; Acute myeloid leukemia; Animal models; Animals; Apoptosis; Basic Medicine; Cancer and Oncology; Cancer och onkologi; Cell Biology; Cell Transformation, Neoplastic; Clinical Medicine; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Hematology; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Human Genetics; Internal Medicine; Klinisk medicin; Latency; Leukemia; Leukemia, Biphenotypic, Acute - genetics; Leukemia, Biphenotypic, Acute - metabolism; Leukemia, Biphenotypic, Acute - pathology; Lymphatic leukemia; Lymphocytes B; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Mice; Mutation; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncology; Progenitor cells; short-communication; Stem cells; Transcription Factors - genetics; Transcription Factors - metabolism; Translocation; Translocation, Genetic; Translocations (Genetics); United States > US; Sweden; Germany
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.470

Translocations involving the mixed lineage leukemia-1 are recurrent events in acute leukemia and associate with lymphoid (ALL), myeloid (AML) or mixed lineage (MLL) subtypes. Despite an association with ALL in humans, murine MLL fusion models are persistently restricted to AML. We here explored this issue using an inducible mixed lineage leukemia-eleven nineteen leukemia (MLL-ENL) mouse model. Although multiple progenitor cell types with myeloid potential are potent AML leukemia-initiating cells, also the earliest lymphoid progenitors were capable of initiating AML. This ability to evoke a latent myeloid potential in the earliest lymphoid progenitors was lost upon further lymphoid commitment. At the same time, more downstream/committed lymphoid precursors also failed to initiate lymphoid leukemia. Co-expression of MLL-ENL with a constitutively active RAS allele, the most common co-mutation in MLL fusion leukemias, could influence on both disease latency and lineage assignment of developing leukemia in what appears to be a mutation-order-dependent manner. Finally, CEBPB-mediated transdifferentation of committed and otherwise leukemia-incompetent B-cell progenitors imbued these cells with leukemic competence for AML. Therefore, apart from providing detailed insight into the differential responsiveness of candidate target cells to a first-hit MLL fusion event, our data warrants caution to therapeutic approaches based on the concept of transdifferentiation.