Preferential development of pre‐B lymphomas with drastically down‐regulated N‐myc in the Eμ‐ret transgenic mice

Abstract

We established one transgenic mouse line which developed pre-B leukemic lymphomas by introducing ret cDNA driven by the SV40 promoter and the mouse immunoglobulin (Ig) enhancer. Lymphomas developed not only in the lymph nodes and the spleen but also in the thymus between the ages of 7 and 21 weeks. Analyses of cell surface phenotypes and Ig gene rearrangement revealed that these tumors were surface IgM-B220+ pre-B lymphomas. The rearrangement pattern of the Ig heavy chain locus indicated that the tumor cells were mono- or oligoclonal. Northern blot analysis showed that the ret transgene was expressed at a high level not only in the tumors but also in the prelymphomatous lymphoid tissues. We found that the expression of N-myc was dramatically down-regulated in the tumor cells, while the expression of c-myc was rather stable. Further experiments demonstrated that ret gene product did not directly down-regulate the expression of N-myc in transformed pre-B cell lines by in vitro transfection assay. From these results, we conclude that under the control of Ig enhancer, the ret transgene affected B lymphocytes at the early maturation stage as a prerequisite for transformation, preferentially generating a unique maturation stage of pre-B lymphomas whose N-myc expression was developmentally down-regulated.

CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

“…Ongoing deletion of all B-lymphoid programmed leukaemia through CD19 immune pressure or genetic ablation reveals the myeloid potential. This is in contrast to the Eμ-RET-driven leukaemia, that is driven by an Eμ-enhancer and lacks a myeloid potential in several publications 41 53 54 , and which retains stable B lineage commitment even with in vivo CD19-CAR immune pressure or in vitro deletion of Ebf1 and Pax5 .…”

The Role of p53 in Suppression of KSHV Cyclin-induced Lymphomagenesis

“…Typically, such immature IgM Ϫ B or DP/TCR low T lymphoma cells are able to escape the boundaries of their normal somatic environment (bone marrow or thymus, respectively) and spread to blood and peripheral organs. Similar attributes are shared by lymphomas arising in many other transgenic models in which oncogenes are targeted to lymphoid tissues, including E-myc (46,47), E-ret (48,49), and lck-M cyclin (44). In all cases, it remains unclear whether the primary action of the oncogenic lesion is to promote cell proliferation and/or to suppress differentiation.…”

Further Characterization of the Sho-saiko-to-Mediated Anti-Tumor Effect on Melanoma Developed in RET-Transgenic Mice

“…The results of our earlier experiments suggested that the RET oncogene product works not only for promoting oncogenesis but also for inducing anti-tumor protective immunity (Ichihara et al, 1995;Kato et al, 1999). As shown in Figure 1(A), growth of transplanted Ret lymphoma cells, which were derived from an Em/RET-transgenic mouse (Iwamoto et al, 1991), was strongly suppressed in recombinant Ret protein-immunized, but not non-immunized, genetically compatible recipient mice. This ®nding corresponds to our previously reported ®nding of Ret protein expressed on tumors acting as a transplantation tumor antigen (Ichihara et al, 1995;Kato et al, 1999).…”