MN1-TEL myeloid oncoprotein expressed in multipotent progenitors perturbs both myeloid and lymphoid growth and causes T-lymphoid tumors in mice
Copyright policy )MN1-TEL myeloid oncoprotein expressed in multipotent progenitors perturbs both myeloid and lymphoid growth and causes T-lymphoid tumors in mice
The MN1-TEL (meningioma 1-translocation-ETS-leukemia) fusion oncoprotein is the product of the t(12;22)(p13;q11) in human myeloid leukemia consisting of N-terminal MN1 sequences, a transcriptional coactivator, fused to C-terminal TEL sequences, an E26-transformation–specific (ETS) transcription factor. To analyze the role of MN1-TEL in leukemogenesis, we created a site-directed transgenic (knock-in) mouse model carrying a conditional MN1-TEL transgene under the control of the Aml1 regulatory sequences. After induction, MN1-TEL expression was detected in both myeloid and lymphoid cells. Activation of MN1-TEL expression enhanced the repopulation ability of myeloid progenitors in vitro as well as partially inhibited their differentiation in vivo. MN1-TEL also promoted the proliferation of thymocytes while it blocked their differentiation from CD4-/CD8- to CD4+/CD8+ in vivo. After long latency, 30% of the MN1-TEL–positive mice developed T-lymphoid tumors. This process was accelerated by N-ethyl-N-nitrosourea–induced mutations. MN1-TEL–positive T-lymphoid tumors showed elevated expression of the Notch-1, Hes-1, c-Myc, and Lmo-2 genes while their Ink4a/pRB and Arf/p53 pathways were impaired, suggesting that these alterations cooperatively transform T progenitors. We conclude that MN1-TEL exerts its nonlineage-specific leukemogenic effects by promoting the growth of primitive progenitors and blocking their differentiation, but cooperative mutations are necessary to fully induce leukemic transformation.
- St. Jude Children's Research Hospital United States
Leukemia, T-Cell, Oncogene Proteins, Fusion, Cell Differentiation, Mice, Transgenic, Gene Expression Regulation, Neoplastic, Survival Rate, Mice, Cell Transformation, Neoplastic, Phenotype, Leukemia, Myeloid, Mutation, Animals, Humans, Lymphocytes, Myeloid Progenitor Cells, Cell Proliferation, Signal Transduction, Transcription Factors
Leukemia, T-Cell, Oncogene Proteins, Fusion, Cell Differentiation, Mice, Transgenic, Gene Expression Regulation, Neoplastic, Survival Rate, Mice, Cell Transformation, Neoplastic, Phenotype, Leukemia, Myeloid, Mutation, Animals, Humans, Lymphocytes, Myeloid Progenitor Cells, Cell Proliferation, Signal Transduction, Transcription Factors
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).26 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!