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Meis2 as a critical player in MN1-induced leukemia
- Source :
- Blood Cancer Journal
- Publication Year :
- 2017
-
Abstract
- Meningioma 1 (MN1) is an independent prognostic marker for normal karyotype acute myeloid leukemia (AML), with high expression linked to all-trans retinoic acid resistance and poor survival. MN1 is also a potent and sufficient oncogene in murine leukemia models, strongly dependent on the MEIS1/AbdB-like HOX protein complex to transform common myeloid progenitors, block myeloid differentiation, and promote leukemic stem cell self-renewal. To identify key genes and pathways underlying leukemic activity, we functionally assessed MN1 cell phenotypic heterogeneity, revealing leukemic and non-leukemic subsets. Using gene expression profiling of these subsets combined with previously published comparisons of full-length MN1 and mutants with varying leukemogenic activity, we identified candidate genes critical to leukemia. Functional analysis identified Hlf and Hoxa9 as critical to MN1 in vitro proliferation, self-renewal and impaired myeloid differentiation. Although critical to transformation, Meis1 knockdown had little impact on these properties in vitro. However, we identified Meis2 as critical to MN1-induced leukemia, with essential roles in proliferation, self-renewal, impairment of differentiation and disease progression in vitro and in vivo. Here, we provide evidence of phenotypic and functional hierarchy in MN1-induced leukemic cells, characterise contributions of Hlf, Hoxa9 and Meis1 to in vitro leukemic properties, and reveal Meis2 as a novel player in MN1-induced leukemogenesis.
- Subjects :
- 0301 basic medicine
Candidate gene
Myeloid
Retinoic acid
Biology
Leukemogenic
03 medical and health sciences
chemistry.chemical_compound
Mice
medicine
Animals
Myeloid Ecotropic Viral Integration Site 1 Protein
Homeodomain Proteins
Oncogene Proteins
Gene knockdown
Leukemia
Oncogene
Gene Expression Regulation, Leukemic
Tumor Suppressor Proteins
Hematology
medicine.disease
3. Good health
Gene expression profiling
030104 developmental biology
medicine.anatomical_structure
Basic-Leucine Zipper Transcription Factors
Oncology
chemistry
Gene Knockdown Techniques
Cancer research
Trans-Activators
Original Article
Subjects
Details
- ISSN :
- 20445385
- Volume :
- 7
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Blood cancer journal
- Accession number :
- edsair.doi.dedup.....ed02ebf5cea7ef8b985b5eae41be79e2