Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway.
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.
Yu
Duonan
D
Departments of Pathobiology, Pathology and Laboratory Medicine, and Animal Biology, University of Pennsylvania, Philadelphia, PA 19104-6051, USA.
Allman
David
D
Goldschmidt
Michael H
MH
Atchison
Michael L
ML
Monroe
John G
JG
Thomas-Tikhonenko
Andrei
A
D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis / Q000235:genetics; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D002448:Cell Adhesion; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics*; D048429:Cell Size; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002999:Clone Cells / Q000637:transplantation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016259:Genes, myc; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000235:genetics; D008214:Lymphocytes / Q000473:pathology*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000473:pathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D051757:PAX5 Transcription Factor; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
D018941:Antigens, CD19; D000943:Antigens, Differentiation; D000944:Antigens, Differentiation, B-Lymphocyte; D039481:CD11b Antigen; D004268:DNA-Binding Proteins; C489921:Ebf1 protein, mouse; D009363:Neoplasm Proteins; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C036763:monocyte-macrophage differentiation antigen; D017493:Leukocyte Common Antigens