Conditional MN1-TEL knock-in mice develop acute myeloid leukemia in conjunction with overexpression of HOXA9.

Abstract

The chromosomal translocation t(12; 22)(p13;q11) in human myeloid leukemia generates an MN1-TEL (meningioma 1-translocation-ETS-leukemia) fusion oncoprotein. This protein consists of N-terminal MN1 sequences, a transcriptional coactivator fused to C-terminal TEL sequences, an ETS (E26 transformation-specific) transcription factor. Enforced expression of MN1-TEL in multipotent hematopoietic progenitors in knock-in mice perturbed growth and differentiation of myeloid as well as lymphoid cells. Depending on obligatory secondary mutations, these mice developed T-cell lympholeukemia. Here we addressed the role of MN1-TEL in myeloid leukemogenesis using the same mouse model. Expression of MN1-TEL enhanced the growth of myeloid progenitors in an interleukin 3/stem cell factor (IL-3/SCF)-dependent manner in vitro whereas 10% of MN1-TEL-expressing mice developed altered myelopoiesis with severe anemia after long latency. Coexpression of MN1-TEL and IL-3, but not SCF, rapidly caused a fatal myeloproliferative disease rather than acute myeloid leukemia (AML). Because MN1-TEL+ AML patient cells overexpress HOXA9 (homeobox A9), we tested the effect of coexpression of MN1-TEL and HOXA9 in mice and found that 90% of MN1-TEL+/HOXA9+ mice developed AML much more rapidly than control HOXA9+ mice. Thus, the leukemogenic effect of MN1-TEL in our knock-in mice is pleiotropic, and the type of secondary mutation determines disease outcome.

• Authors: Hiroyuki Kawagoe, Gerard C Grosveld
• Journal: Blood (Blood) Vol. 106 Issue 13 Pg. 4269-77 (Dec 15 2005) ISSN: 0006-4971 [Print] United States
• PMID: 16105979 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• ETS translocation variant 6 protein
• Homeodomain Proteins
• Mn1 protein, mouse
• Oncogene Proteins
• Proto-Oncogene Proteins c-ets
• Proto-Oncogene Proteins c-myc
• Repressor Proteins
• Trans-Activators
• Tumor Suppressor Proteins
• homeobox protein HOXA9

Topics

• Animals
• Cell Proliferation
• Cells, Cultured
• Cytokines (pharmacology)
• Gene Expression Regulation, Neoplastic
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Leukemia, Myeloid, Acute (genetics, metabolism, pathology)
• Mice
• Mice, Transgenic
• Myeloid Progenitor Cells (cytology, drug effects, metabolism)
• Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-ets (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Repressor Proteins (genetics, metabolism)
• Trans-Activators
• Transgenes (genetics)
• Tumor Suppressor Proteins