Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3529-3536
RAPID COMMUNICATION
The Fetal Origin of B-Precursor Leukemia in the Eµ-ret Mouse
Xiang-Xing Zeng,
Haige Zhang,
Richard R. Hardy, and
Robert Wasserman
From the Division of Oncology, The Children's Hospital of
Philadelphia, and Department of Pediatrics, The University of
Pennsylvania School of Medicine, Philadelphia, PA; and the Institute
for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA.
Before the clinical onset of B-precursor lymphoblastic leukemia,
Eµ-ret mice have an expansion of late pro-B cells
(CD45R+CD43+CD24+BP-1+)
within the bone marrow. To characterize the early effects of the
transgene product on lymphopoiesis, we initially sequenced the Ig heavy
chain (IgH) rearrangements within the late pro-B cells in 24-day-old
Eµ-ret and transgene negative mice. In both mouse populations, the
IgH rearrangements were polyclonal, predominately nonproductive, and
exhibited similar V, D, and J gene usage. However, the frequency of N
regions, a marker of postnatal lymphopoiesis, was notably different. At
the VD junction, N regions were found in 25 of 25 (100.0%)
rearrangements from transgene-negative mice compared with 12 of 36 (33.3%) rearrangements from Eµ-ret mice. At the DJ junction, N
regions were found in 21 of 25 (84.0%) rearrangements from transgene
negative mice compared with 4 of 36 (11.1%) rearrangements from
Eµ-ret mice. Subsequently, we sequenced the clonal IgH rearrangements from 9 leukemias that developed in 10-to 38-week-old mice and found
that 7 leukemias had a least 1 rearrangement that lacked N regions at
the DJ junction. In addition, V replacement events were observed in the
1 leukemia studied in detail. Terminal deoxynucleotidyl transferase,
the enzyme responsible for N region addition, was expressed at markedly
lower levels in late pro-B cells from 7- to 10-day-old Eµ-ret mice
compared with transgene-negative mice. Examination of fetal
lymphopoiesis in Eµ-ret mice identified a relative increase in early
(CD45R+CD43+CD24+BP-1
)
and late pro-B cells and a decrease in more differentiated
CD43 B-lineage cells. Fetal early pro-B cells from
Eµ-ret mice proliferated threefold to fivefold greater but
differentiated to a lesser extent than those from transgene negative
mice when cultured in vitro with interleukin-7. These data suggest that
the B precursor leukemias in adult Eµ-ret mice arise from the progeny
of pro-B cells generated in utero.
