RRC ID 11033
Author Kawagoe H, Grosveld GC.
Title Conditional MN1-TEL knock-in mice develop acute myeloid leukemia in conjunction with overexpression of HOXA9.
Journal Blood
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.
Volume 106(13)
Pages 4269-77
Published 2005-12-15
DOI 10.1182/blood-2005-04-1679
PII S0006-4971(20)67743-6
PMID 16105979
PMC PMC1895240
MeSH Animals Cell Proliferation Cells, Cultured Cytokines / pharmacology Gene Expression Regulation, Neoplastic Homeodomain Proteins / genetics Homeodomain Proteins / metabolism* Humans Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / metabolism* Leukemia, Myeloid, Acute / pathology* Mice Mice, Transgenic Myeloid Progenitor Cells / cytology Myeloid Progenitor Cells / drug effects Myeloid Progenitor Cells / metabolism Oncogene Proteins / genetics Oncogene Proteins / metabolism* Proto-Oncogene Proteins c-ets / genetics Proto-Oncogene Proteins c-ets / metabolism* Proto-Oncogene Proteins c-myc / metabolism Repressor Proteins / genetics Repressor Proteins / metabolism* Trans-Activators Transgenes / genetics Tumor Suppressor Proteins
IF 17.794
Times Cited 33
DNA material pCAmKL (RDB1528) pCAmIL3 (RDB1506)