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The Evolution of B Precursor Leukemia in the Eµ-ret Mouse
Robert Wasserman,
Xiang-Xing Zeng, and
Richard R. Hardy
From the Division of Oncology, The Children's Hospital of
Philadelphia; the Department of Pediatrics, The University of
Pennsylvania School of Medicine, Philadelphia; and the Institute for
Cancer Research, Fox Chase Cancer Center, Philadelphia, PA.
Eµ-ret mice carrying an RFP/RET fusion gene under the
transcriptional control of the immunoglobulin heavy chain enhancer
develop B lineage leukemias/lymphomas. We have characterized B-cell
development in these mice before the onset of clinical disease to
determine the steps involved in leukemogenesis. Flow cytometry reveals
that the
CD45R+CD43+CD24+BP-1+
late pro-B-cell population is markedly expanded in the bone marrow of
3- to 5-week-old Eµ-ret mice. Compared with late pro-B cells from
transgene-negative mice, Eµ-ret late pro-B cells have a limited capacity to differentiate in interleukin (IL)-7 and a higher incidence of VDJ rearrangements, but a similar cell cycle profile. In contrast, CD45R+CD43+CD24+BP-1
early pro-B cells from 3- to 5-week-old Eµ-ret mice, which also express the RFP/RET transgene, differentiate in IL-7 similarly to their
normal counterparts. Furthermore, early pro-B cells from Eµ-ret and
transgene-negative mice have an identical pattern of growth inhibition
when exposed to interferons (IFNs)- / and - , whereas,
pro-B-cell leukemia lines derived from Eµ-ret mice are markedly less
sensitive to growth inhibition by these IFNs. In 13-week-old
well-appearing Eµ-ret mice, late pro-B cells upregulate CYCLIN D1
expression and downregulate CASPASE-1 expression in a pattern that
correlates with the emergence of B precursor cells in the peripheral
blood and the loss of other B lineage subsets in the bone marrow. Taken
together, these results suggest that the expression of the RFP/RET
transgene initially prevents the normal elimination of late pro-B
cells with nonproductive rearrangements. Secondary events that
simultaneously disturb the normal transcriptional regulation of genes
involved in the control of the cell cycle and apoptosis may allow for
subsequent malignant transformation within the expanded late
pro-B-cell population.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 273-282
© 1998 by The American Society of Hematology.
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