To the Editor:

The perspectives article, “Seed Versus Soil: The Importance of the Target Cell for Transgenic Models of Human Leukemias,” by Westervelt and Ley,1 highlighted a number of important issues regarding the use of transgenic murine models for leukemia research. One, the potential role of variation among mouse strains, was alluded to in the discussion of data from several PML/RARA fusion gene models of acute promyelocytic leukemia in which the investigators state that “the potential role of mouse strain differences contributing to the different observed phenotypes cannot be formally excluded at this time.” Indeed, several inbred strains of mice have been shown to exhibit significant differences in the levels of hematopoietic stem cells (HSCs) in bone marrow, as measured by long-term culture-initiating cell assay (LTC-IC), with C57BL/6 (B) and DBA/2 (D) mice differing by more than 10-fold and BALB/c (C) at intermediate levels.2 The variables causing such striking inter-strain differences in HSC levels may also be expected to exert some influence on the phenotypic effects due to the expression of a leukemia-related transgene in the HSC cell compartment.

Inter-strain variation in murine HSC levels may also be exploited to identify such variables. Performing a genetic reanalysis with current mapping information of previous data from 26 BXD recombinant inbred (RI) strains2 with MapManager software,3 using an additive regression model with no control for other quantitative trait loci (QTLs), has nominated 12 loci on 6 chromosomes at theP < .01 level linked to HSC level (Table 1). Several interesting candidate genes with potential relevance to HSCs that map close to nominated QTLs were also identified. Although the RI approach can be fraught with false-positive results and require confirmation, QTL nominations near 2 chemokine genes on chromosome 1, an interleukin gene cluster and granulocyte-macrophage colony-stimulating factor on chromosome 11, and a small inducible cytokine gene complex on chromosome 11, are highly suggestive and supported by functional approaches,4-6 including the recent demonstration of the role of chemokine receptor 4 (CXCR4) in hematopoietic reconstitution of human HSCs in immune deficient mice.7 Such data suggest that the inter-strain variation in HSC levels may be multifactorial and that the murine host may not be a passive nonparticipant in either transgenic or HSC engraftment and repopulation experiments. The identification of the specific inter-strain differences related to HSCs may, thus, be important in the design and interpretation of murine transgenic models of leukemias.

1
Westervelt
P
Ley
TJ
Seed versus soil: The importance of the target cell for transgenic models of human leukemias.
Blood
93
1999
2143
2
Muller-Sieburg
CE
Riblet
RJ
Genetic control of the frequency of hematopoietic stem cells in mice: Mapping of a candidate locus to chromosome 1.
J Exp Med
183
1996
1141
4
Blum
S
Forsdyke
RE
Forsdyke
DR
Three human homologs of a murine gene encoding an inhibitor of stem cell proliferation.
DNA Cell Biol
9
1990
589
5
Goan
SR
Schwarz
K
von Harsdorf
S
von Schilling
C
Fichtner
I
Junghahn
I
Just
U
Herrmann
F
Fibroblasts retrovirally transfected with the human IL-3 gene initiate and sustain multilineage human hematopoiesis in SCID mice: Comparison of CD34-enriched vs CD34-enriched and in vitro expanded grafts.
Bone Marrow Transplant
18
1996
513
6
Cashman
JD
Lapidot
T
Wang
JC
Doedens
M
Shultz
LD
Lansdorp
P
Dick
JE
Eaves
CJ
Kinetic evidence of the regeneration of multilineage hematopoiesis from primitive cells in normal human bone marrow transplanted into immunodeficient mice.
Blood
89
1997
4307
7
Peled
A
Petit
I
Kollet
O
Magid
M
Ponomaryov
T
Byk
T
Nagler
A
Ben-Hur
H
Many
A
Shultz
L
Lider
O
Alon
R
Zipori
D
Lapidot
T
Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.
Science
283
1999
845
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