Insights from transgenic mice regarding the role ofbcl-2 in normal and neoplastic lymphoid cells

Abstract

The bcl-2 gene was first discovered by molecular analysis of the 14;18 chromosome translocation which is the hallmark of most cases of human follicular lymphoma. To date, it is unique among proto-oncogenes because, rather than promoting cell proliferation, it fosters cell survival. This review summarizes the impact of constitutive bcl-2 expression on the development and function of lymphocytes as well as their malignant transformation. Expression of a bcl-2 transgene in the B lymphoid compartment profoundly perturbed homeostasis and, depending on the genetic background, predisposed to a severe autoimmune disease resembling human systemic lupus erythematosus. T lymphoid cells from bcl-2 transgenic mice were remarkably resistant to diverse cytotoxic agents. Nevertheless, T lymphoid homeostasis was unaffected and tolerance to self was maintained. Expression of high levels of Bcl-2 facilitated the development of B lymphoid tumours but at relatively low frequency and with long latency. Co-expression of myc and bcl-2, on the other hand, promoted the rapid onset of novel tumours which appeared to derive from a lympho-myeloid stem or progenitor cell. Introduction of the bcl-2 transgene into scid mice facilitated the survival and differentiation of pro-B but not pro-T cells, suggesting that a function necessary to supplement or complement the action of Bcl-2 is expressed later in the T than the B lineage. Crosses of the bcl-2 transgenic mice with p53-/- mice have addressed whether loss of p53 function and gain of bcl-2 function are synergistic for lymphoid cell survival.

High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology

“…Bcl-2 has been found to induce tumor growth and confer resistance to chemotherapeutic agents in xenograft models of human non small cell lung cancer (NSCLC) [8-10] and Bcl-2 inhibition seems to contribute to reversal of drug resistance in a variety of cancer cell line models[11,12]. Demonstration of the role of Bcl-2 in oncogenesis has prompted the development of drugs targeting Bcl-2 for degradation[13]. Despite the promising preclinical studies supporting a critical role of Bcl-2 in chemoresistance, addition of anti-Bcl-2 antisense oligonucleotide therapies to standard chemotherapy was not correlated with a survival benefit [14-18].…”

Ras activation leads to cell proliferation or apoptotic cell death upon interleukin‐2 stimulation or lymphokine deprivation, respectively

“…A number of molecules that either promote or prevent cell death have been characterized. Members of the former include the cell surface molecule CD95/Fas/APO-l , the intracellular protein Bax [4,9], the orphan steroid receptor N u r n [lo, 111, the short splice variant of the bcl-x gene product (Bcl-xs) [2], the protease interleukin-lg converting enzyme (ICE) [12,131, and the larger form of its homolog ICH-1 [14]. Other molecules are potent inhibitors of cell death, including the Bcl-2 protein [l, 2, 4, 91, the large form of Bcl-x (Bcl-xL) [2], the short splice variant of ICH-1 [14], and the DAD1 protein [ 151.…”

Normal and leukemic hematopoiesis: Are leukemias a stem cell disorder or a reacquisition of stem cell characteristics?

“…Hence, the increased survival provided by enforced Bcl-2 family member expression may allow sufficient time for the acquisition of additional oncogenic mutations, a mechanism thought to underlie the transition from chronic to acute leukemia (94). Whereas the deregulation of Bcl-2 expression is found in many human cancers, overexpression of Bcl-2 in a transgenic mouse model has been found to be relatively benign in terms of cellular transformation (95). Hence, enforced expression of Bcl-2 in the myeloid lineage with the hMRP8 promoter leads to a disease that is similar to human chronic myelomonocytic leukemia, including monocytosis, splenomegaly and neutropenia as the mice age (96).…”