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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-06-1797.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1950-1955
NEOPLASIA
Oscillation between B-lymphoid and myeloid lineages in
Myc-induced hematopoietic tumors following spontaneous
silencing/reactivation of the EBF/Pax5 pathway
Duonan Yu,
David Allman,
Michael H. Goldschmidt,
Michael L. Atchison,
John G. Monroe, and
Andrei Thomas-Tikhonenko
From the Departments of Pathobiology, Pathology and
Laboratory Medicine, and Animal Biology, University of Pennsylvania,
Philadelphia, PA.
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.
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