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MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment
- Source :
- Oncogene. 36:3207-3212
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Myeloid
Lineage (genetic)
Oncogene Proteins, Fusion
Biology
Translocation, Genetic
Mice
03 medical and health sciences
hemic and lymphatic diseases
Genetics
medicine
Animals
Progenitor cell
neoplasms
Molecular Biology
Acute leukemia
Transdifferentiation
Histone-Lysine N-Methyltransferase
Cell cycle
medicine.disease
Leukemia, Biphenotypic, Acute
DNA-Binding Proteins
Disease Models, Animal
Leukemia
Cell Transformation, Neoplastic
030104 developmental biology
medicine.anatomical_structure
Immunology
Myeloid-Lymphoid Leukemia Protein
Transcription Factors
Lymphoid leukemia
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....926c7a34ea92e0eabf80e689f2169d32