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Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential
- Source :
- Genes & Development. 21:2762-2774
- Publication Year :
- 2007
- Publisher :
- Cold Spring Harbor Laboratory, 2007.
-
Abstract
- Oncogenic mutations of the MLL histone methyltransferase confer an unusual ability to transform non-self-renewing myeloid progenitors into leukemia stem cells (LSCs) by mechanisms that remain poorly defined. Misregulation of Hox genes is likely to be critical for LSC induction and maintenance but alone it does not recapitulate the phenotype and biology of MLL leukemias, which are clinically heterogeneous—presumably reflecting differences in LSC biology and/or frequency. TALE (three-amino-acid loop extension) class homeodomain proteins of the Pbx and Meis families are also misexpressed in this context, and we thus employed knockout, knockdown, and dominant-negative genetic techniques to investigate the requirements and contributions of these factors in MLL oncoprotein-induced acute myeloid leukemia. Our studies show that induction and maintenance of MLL transformation requires Meis1 and is codependent on the redundant contributions of Pbx2 and Pbx3. Meis1 in particular serves a major role in establishing LSC potential, and determines LSC frequency by quantitatively regulating the extent of self-renewal, differentiation arrest, and cycling, as well as the rate of in vivo LSC generation from myeloid progenitors. Thus, TALE proteins are critical downstream effectors within an essential homeoprotein network that serves a rate-limiting regulatory role in MLL leukemogenesis.
- Subjects :
- Time Factors
Myeloid
Context (language use)
Biology
Mice
Proto-Oncogene Proteins
hemic and lymphatic diseases
Tumor Cells, Cultured
Genetics
medicine
Animals
Humans
Myeloid Ecotropic Viral Integration Site 1 Protein
Hox gene
Cell Proliferation
Homeodomain Proteins
Mice, Knockout
Gene Expression Regulation, Leukemic
Myeloid leukemia
medicine.disease
Neoplasm Proteins
DNA-Binding Proteins
Genes, cdc
Mice, Inbred C57BL
Repressor Proteins
Leukemia, Myeloid, Acute
Leukemia
Cell Transformation, Neoplastic
medicine.anatomical_structure
Histone methyltransferase
Neoplastic Stem Cells
Cancer research
Myeloid-Lymphoid Leukemia Protein
Stem cell
K562 Cells
Neoplasm Transplantation
Developmental Biology
Subjects
Details
- ISSN :
- 15495477 and 08909369
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Genes & Development
- Accession number :
- edsair.doi.dedup.....612acbc9e6565167ebbbe925d7ed25a0