Allelic loss on chromosome 4 (Lyr2/TLSR5) is associated with myeloid, B–lympho-myeloid, and lymphoid (B and T) mouse radiation-induced leukemias

Abstract

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)

Alternative promoters and polyadenylation regulate tissue‐specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis

“…These results provide direct evidence confirming the previous assignment of HEMGN to chromosome 9q22 by database mining (Yang et al, 2001). Of particular interest are the following observations: that HEMGN is located near the minimally deleted region of mouse radiation-induced leukemias (14.5-17.9 cM) on chromosome 4 A5-B2 (Cleary et al, 2001), and that chromosome locus 9q22 is a region containing a cluster of human leukemia breakpoints and genes important for leukemogenesis (Sreekantaiah et al, 1989). Moreover, familial hemophagocytic lymphohistiocytosis (FHL1), a disorder of hematopoietic cells, also maps to 9q21.3-q22 (Ohadi et al, 1999).…”

Low-penetrance genetic susceptibility and resistance loci implicated in the relative risk for radiation-induced acute myeloid leukemia in mice

“…During the course of these studies, 54 early pre-B mixed-lineage lymphomyeloid leukemias (L-MLs) were diagnosed 19 in the irradiated backcross mice. The r-AML and L-ML loss of heterozygosity profiles on chromosomes 2 and 4 differ, 19 suggesting that they represent 2 distinct hemopoietic malignancies, and mice affected with L-ML are included in the unaffected mice that died of other causes (Tables 2-3).…”

“…DNA was prepared from control (tail, kidney, or both) and leukemic spleen essentially as described. 17,19 …”

“…The r-AML and L-ML loss of heterozygosity profiles on chromosomes 2 and 4 differ, 19 suggesting that they represent 2 distinct hemopoietic malignancies, and mice affected with L-ML are included in the unaffected mice that died of other causes (Tables 2-3). However, further evidence to support the proposition that 2 distinct leukemogenic processes are involved can be inferred when the 4 genotype combinations for the most informative loci on chromosomes 1 (D1Mit150; 1 hom or 1 het ) and 6 (D6Mit384; 6 hom or 6 het ) were compared in r-AML-and L-MLaffected mice.…”

“…17,19 Genome-wide screen for linkage Microsatellite primer sequences were from the Whitehead Institute, 20 and genetic positions were from the 2000 Chromosome Committee Reports (Jackson Laboratory 21 ). Five hundred eighty-seven microsatellite markers across the 19 mouse autosomes were screened for informative polymorphisms in the inbred CBA/H and C57BL/6 mice.…”