The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells.

Abstract

Mice transgenic for a c-myc gene driven by the IgH enhancer (E mu-myc) were shown to almost invariably develop lymphomas, 90% succumbing in the first 5 mo of life. The tumors typically presented as rapidly progressive lymphadenopathy with thymic involvement and were highly malignant by transplantation assay. Morphologically, they were lymphoblastic lymphomas, usually accompanied by lymphoid leukemia and granulocytosis, and were distinct from the tumors that arose much later in 37% of nontransgenic mice of the same (C57BL/6 x SJL)F2 genetic background. Cell-surface markers on 31 E mu-myc tumors identified 52% as pre-B lymphomas, 29% as mixed pre-B and B lymphomas, and 19% as B lymphomas. The tumors appeared to arise at random from a population of pre-B cells expanded by constitutive expression of the myc transgene. A majority of the animals initiated malignancy at the rate of 17% per week. The rate at which the cycling, benign pre-B cells spontaneously convert to malignancy was estimated to about 10(-10) per cell per generation. A transient leukocytosis identified in young E mu-myc mice was developed into a rapid assay for inheritance of the transgene.

The BCL-2 protein family, BH3-mimetics and cancer therapy

“…81 Early in life, these mice contain abnormally increased numbers of large, cycling B-cell progenitors, 82 which comprise the nascent neoplastic cells. 83 Upon acquisition of oncogenic mutations that cooperate with MYC in neoplastic transformation, clonal malignant pre-B or sIg + B lymphomas emerge from the pool of preleukaemic B lymphoid cells. 83 On a C57BL/6 background, median (50%) survival is~110 days, and all animals succumb to lymphoma within~350-400 days.…”

“…83 Upon acquisition of oncogenic mutations that cooperate with MYC in neoplastic transformation, clonal malignant pre-B or sIg + B lymphomas emerge from the pool of preleukaemic B lymphoid cells. 83 On a C57BL/6 background, median (50%) survival is~110 days, and all animals succumb to lymphoma within~350-400 days. Tumour cells from lymphoma-bearing mice can be readily transplanted into syngeneic (immune-competent) recipients or adapted to grow indefinitely in vitro as cell lines.…”

“…Tumour cells from lymphoma-bearing mice can be readily transplanted into syngeneic (immune-competent) recipients or adapted to grow indefinitely in vitro as cell lines. 81,83 These two features and the ability to identify and study a preneoplastic cell population (see above) made this the most widely used animal model of human cancer (41400 publications).…”

V-myc in a simple, single gene retroviral vector causes rapid induction of leukemia and concomitant apoptosis following bone marrow transplantation

“…3,4 Aberrant expression of c-myc has been implicated in a wide variety of experimentally induced tumors. 5 The precise mechanism(s) by which myc activation contributes to oncogenesis is not completely defined. Myc is a DNA-binding phosphoprotein which can function as a transcriptional activator.…”

AID and RAG1 do not contribute to lymphomagenesis in Eμ c-myc transgenic mice

“…To investigate the oncogenic role of c-myc, Em c-myc transgenic (Tg) mice were generated by coupling the c-myc gene with the Ig-m enhancer (Adams et al, 1985). B-cell lymphomas arise in these mice in a stochastic manner between 6 and 83 weeks of age (Harris et al, 1988), derive from different stages of B-cell development and are usually monoclonal in origin (Adams et al, 1985;Prasad et al, 1996;Egle et al, 2004). These data indicate that constitutive expression of c-myc alone is not sufficient to induce tumors and that secondary genetic lesions are required.…”