Inbred CBA/H mice are susceptible to radiation-induced acute myeloid leukemia (r-AML), and C57BL/6 mice are resistant. A genome-wide screen for linkage between genotype and phenotype (r-AML) of 67 affected (CBA/H ؋ C57BL/ 6)F1 ؋ CBA/H backcross mice has revealed at least 2 suggestive loci that contribute to the overall lifetime risk for r-AML. Neither is necessary or sufficient for r-AML, but relative risk is the net effect of susceptibility (distal chromosome 1) and resistance (chromosome 6) loci. An excess of chromosome 6 aberrations in mouse r-AML and bone marrow cells up to 6 months after irradiation in vivo suggests the locus confers a proliferative advantage during the leukemogenic process. The stem cell frequency regulator 1 (Scfr1) locus maps to distal chromosome 1 and determines the frequency of hemopoietic stem cells (HSCs) in inbred mice, suggesting that target size may be one factor in determining the relative susceptibility of inbred mice to r

The CBA/H mouse model of radiationinduced acute myeloid leukemia (AML) was re-examined using molecular approaches. In addition to the typical promyelocytic AMLs, 34% were reclassified as early pre-B lympho-myeloid leukemias (L-ML) based on leukemic blood cell morphology, immunoglobulin heavy-chain gene re-arrangements (IgH R ), or expression of both lymphoid (Vpre-B1 and Rag1) and myeloid (myeloperoxidase and lysozyme M) genes. Allelic loss on chromosome 4 was frequently detected in AMLs (53%) and L-MLs (more than 95%), and the preferential loss of the maternally transmitted allele suggests the locus may be imprinted. A minimally deleted region (MDR) maps to a 3.4-cM interval, which is frequently deleted in radiation-induced thymic lymphomas (TLSR5) and contains a recessive, maternally transmitted genetic locus (Lyr 2) that confers resistance to spontaneous and radiation-induced pre-B and T cell lymphomas, suggesting they are one and the same. Thus, the Lyr 2/TLSR5 locus is frequently implicated in myeloid, lymphoid (B and T), and mixed-lineage mouse leukemias and lymphomas. Epigenetic inactivation of one Lyr2/TLSR5 allele during normal mouse development suggests that only a single hit is required for its inactivation during leukemogenesis, and this may be a significant contributing factor to the efficiency of the leukemogenic process in the mouse. (Blood. 2001;98:1549-1554)

Thymic lymphoma is a very common spontaneous and/or induced malignancy in both inbred mice and in transgenic mouse models of human cancer. Although a thymic lymphoma is defined as thymus-dependent T-cell malignancy, diagnostic criteria vary between studies and considerable heterogeneity has been reported. To define and classify the thymic lymphomas that arose in our study of X-irradiated (CBA/HxC57BL/6)F1, F1 backcross and F1 intercross mice, 66 thymic lymphomas were immunogenotyped for immunoglobulin heavy chain (IgH) and T-cell receptor beta (TCRbeta) gene rearrangements, and/or analysed for expression of lineage-specific markers and allelic loss on chromosome 4. The data indicate that 33% of the thymic lymphomas are very similar to mouse radiation-induced acute myeloid (AML) and mixed lineage (IgH(R), TCRbeta(G)) pre-B lympho-myeloid (L-MLs) leukaemias, 33% are mixed lineage (IgH(R), TCRbeta(R)) B/T lymphoid and <33% can be described as single lineage (IgH(G), TCRbeta(R)) T-cell malignancies. As the myeloid and L-ML leukaemias are not thymus-dependent this suggests that a malignant myeloid or pre-B lympho-myeloid cell can colonize the spleen to give an AML or L-ML leukaemia, or can colonize the thymus where TCRbeta gene rearrangement(s) may be induced to give the mixed lineage thymic lymphomas. Thus, assuming the single lineage T-cell thymic lymphomas fulfil the criteria of a thymus-dependent T-cell malignancy, thymic lymphomas are comprised of at least three distinct malignancies.

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