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Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway.
- Source :
-
Blood [Blood] 2003 Mar 01; Vol. 101 (5), pp. 1950-5. Date of Electronic Publication: 2002 Oct 24. - Publication Year :
- 2003
-
Abstract
- B lymphomagenesis is an uncontrolled expansion of immature precursors that fail to complete their differentiation program. This failure could be at least partly explained by inappropriate expression of several oncogenic transcription factors, such as Pax5 and Myc. Both Pax5 and c-Myc are implicated in the pathogenesis of non-Hodgkin lymphomas. To address their role in lymphomagenesis, we analyzed B-cell lymphomas derived from p53-null bone marrow progenitors infected in vivo by a Myc-encoding retrovirus. All Myc-induced lymphomas invariably maintained expression of Pax5, which is thought to be incompatible with terminal differentiation. However, upon culturing in vitro, several cell lines spontaneously down-regulated Pax5 and its target genes CD19, N-Myc, and MB1. Unexpectedly, other B-cell markers (eg, CD45R) were also down-regulated, and markers of myeloid lineage (CD11b and F4/80 antigen) were acquired instead. Moreover, cells assumed the morphology reminiscent of myeloid cells. A pool of F4/80-positive cells as well as several single-cell clones were obtained and reinjected into syngeneic mice. Remarkably, pooled cells rapidly re-expressed Pax5 and formed tumors of relatively mature lymphoid phenotype, with surface immunoglobulins being abundantly expressed. Approximately half of tumorigenic single-cell clones also abandoned myeloid differentiation and gave rise to B lymphomas. However, when secondary lymphoma cells were returned to in vitro conditions, they once again switched to myeloid differentiation. This process could be curbed via enforced expression of retrovirally encoded Pax5. Our data demonstrate that some Myc target cells are bipotent B-lymphoid/myeloid progenitors with the astonishing capacity to undergo successive rounds of lineage switching.
- Subjects :
- Animals
Antigens, CD19 biosynthesis
Antigens, CD19 genetics
Antigens, Differentiation biosynthesis
Antigens, Differentiation genetics
Antigens, Differentiation, B-Lymphocyte biosynthesis
Antigens, Differentiation, B-Lymphocyte genetics
CD11b Antigen biosynthesis
CD11b Antigen genetics
Cell Adhesion
Cell Differentiation
Cell Size
Cell Transformation, Neoplastic genetics
Clone Cells transplantation
DNA-Binding Proteins genetics
Genes, myc
Leukocyte Common Antigens biosynthesis
Leukocyte Common Antigens genetics
Lymphoma, B-Cell genetics
Mice
Mice, Inbred C57BL
Neoplasm Proteins biosynthesis
Neoplasm Proteins genetics
Neoplasm Transplantation
PAX5 Transcription Factor
Receptors, Antigen, B-Cell biosynthesis
Receptors, Antigen, B-Cell genetics
Recombinant Fusion Proteins physiology
Transcription Factors genetics
Tumor Cells, Cultured metabolism
Tumor Cells, Cultured pathology
Cell Lineage genetics
DNA-Binding Proteins physiology
Gene Expression Regulation, Neoplastic
Gene Silencing
Lymphocytes pathology
Lymphoma, B-Cell pathology
Myeloid Cells pathology
Trans-Activators physiology
Transcription Factors physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 101
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 12406913
- Full Text :
- https://doi.org/10.1182/blood-2002-06-1797