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.
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 x NZW) F1 mice, while H-2(d/z) heterozygosity predisposes to autoimmune disease, H-2(z/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.
Hamano
Y
Y
Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Hirose
S
S
Ida
A
A
Abe
M
M
Zhang
D
D
Kodera
S
S
Jiang
Y
Y
Shirai
J
J
Miura
Y
Y
Nishimura
H
H
Shirai
T
T
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000473:pathology*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006183:H-2 Antigens / Q000235:genetics*; D006239:Haplotypes; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D008815:Mice, Inbred Strains; D009857:Oncogenes
D006183:H-2 Antigens