Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3772-3779
Susceptibility Alleles for Aberrant B-1 Cell Proliferation Involved
in Spontaneously Occurring B-Cell Chronic Lymphocytic Leukemia in a
Model of New Zealand White Mice
Yoshitomo Hamano,
Sachiko Hirose,
Akinori Ida,
Masaaki Abe,
Danqing Zhang,
Sanki Kodera,
Yi Jiang,
Jun Shirai,
Yuko Miura,
Hiroyuki Nishimura, and
Toshikazu Shirai
From the Department of Pathology, Juntendo University School of
Medicine, Tokyo, Japan; Core Research for Evolutional Science and
Technology, Japan Science and Technology Corp, Kawaguchi,
Japan; the Department of Obstetrics and Gynecology, Hyogo
College of Medicine, Hyogo, Japan; and Toin Human Science and
Technology Center, Toin University of Yokohama, Yokohama, Japan.
B-cell chronic lymphocytic leukemia (B-CLL) and autoimmune disease
are a related event, and genetic factors are linked to both diseases.
As B-CLL is mainly of B-1 cell type that participates in autoantibody
production, genetically-determined regulatory abnormalities in
proliferation and/or differentiation of B-1 cells may determine
their fate. We earlier found that, in H-2-congenic (NZB × NZW) F1
mice, while H-2d/z heterozygosity predisposes to autoimmune
disease, H-2z/z homozygosity predisposes to B-CLL. Studies
also suggested the involvement of non-H-2-linked NZW allele(s) in
leukemogenesis. Using H-2-congenic NZW and B10 mouse strains, their F1
and backcross progeny, we have now identified three major NZW
susceptibility loci for abnormal proliferation of B-1 cells, which form
the basis of leukemogenesis; one H-2-linked locus on chromosome 17 and
the other two non-H-2-linked loci, each on chromosome 13 and
chromosome 17. Each susceptibility allele functioned independently, in
an incomplete dominant fashion, the sum of effects determining the extent of aberrant B-1 cell frequencies. The development of leukemia was associated with age-related increase in B-1 cell frequencies in the
blood. Thus, these alleles probably predispose B-1 cells to accumulate
genetic alterations, giving rise to B-CLL. Potentially important
candidate genes and correlation of the findings with autoimmune disease
are discussed.
