A non-transgenic mouse model for B-cell lymphoma: in vivo infection of p53-null bone marrow progenitors by a Myc retrovirus is sufficient for tumorigenesis

Abstract

The c-Myc oncoprotein is strongly implicated in B-cell neoplasms such as human Burkitt lymphomas and mouse plasmocytomas. Transgenic mice in which the myc gene is juxtaposed to an immunoglobulin enhancer (Em-myc) also develop B-cell lymphomas, but relatively late in life. In addition, these neoplasms are invariably clonal, suggesting the involvement of additional mutations. Such mutations frequently aect the p53 tumour suppressor gene or its positive regulator Arf, hinting that inactivation of the p53 pathway might be the second hit required for the progression towards malignancy. However, even tumours arising in Em-myc/Arf-null animals are thought to be clonal. This observation raised doubts whether overexpression of Myc in p53-null B-cell precursors is sucient for tumorigenesis. To address this question, we have established a new, non-transgenic mouse model of B-lymphoma. This model is based on isolation of primary bone marrow (BM) cells, admixing them with packaging cells producing a Myc-encoding retrovirus (LMycSN), and subcutaneous injection into a host with which BM cells are syngeneic. Predictably, wild type BM cells infected in vivo by LMycSN were not tumorigenic. However, LMycSN-infected p53-null BM cells readily gave rise to B-cell lymphomas composed predominantly of late pro-B/small pre-B-cells. In these tumours, heavy chain gene rearrangements were analysed using two independent PCR-based assays. All neoplasms with DJrearrangements were found to be polyclonal. This result suggests that inactivation of p53 and overexpression of Myc is all that is necessary for the development of fulledged B-lymphomas. Our model would also be instrumental in assessing the transforming potential of Myc mutants and in studying cooperation between Myc and other oncogenes.

Activation of Transferrin Receptor 1 by c-Myc Enhances Cellular Proliferation and Tumorigenesis

“…We investigated whether c-Myc regulates TFRC1 expression levels in a murine B-cell lymphoma model, which is based on retroviral transduction of p53-null bone marrow cells with a Myc-encoding retrovirus (25,59,61). Using MycER retroviruses, which express a chimeric protein of c-Myc and the hormone binding domain of the estrogen receptor, neoplasms were generated in animals whose exponential growth was contingent upon continuous administration of 4-hydroxytamoxifen (4-OHT) (13,60).…”

Inactivation of the ARF–MDM-2–p53 pathway in sporadic Burkitt's lymphoma in children

“…19,20 Deletion of this safeguard mechanism greatly accelerates lymphomagenesis and only p53-null bone marrow cells infected with an MYC encoding retrovirus are tumorigenic. [19][20][21] Recently, the ARF-MDM-2-p53 apoptotic pathway has been found to be altered in all 18 BL cell lines tested for deletion of ARF, overexpression of MDM-2 or mutations in the p53 gene. 22 Based on these data from murine models and cell lines, the inactivation of the p53 pathway is considered to be the conditio sine qua non second hit for the progression of MYC overexpressing hyperproliferative cells towards a clinical manifest BL.…”

Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway

“…To answer these questions, we drew upon our recently developed model for B-cell lymphoma based on the infection of p53-null bone marrow progenitors with a retrovirus encoding the Myc oncoprotein. 21 Using this approach, we have generated neoplastic lines that exclusively expressed B-cell markers when passaged in vivo. However, several of them, obtained from independently derived tumors, spontaneously acquired myeloid markers upon culturing in vitro.…”