T cells induce terminal differentiation of transformed B cells to mature plasma cell tumors.

Abstract

Major interest in the analysis of mature plasma cell neoplasias of mice and humans has focused on identification of precursor cells that give rise to mature malignant plasma cells. Although several laboratories have recently suggested that such cells are present in the granulomas of pristane-treated mice and the bone marrow of some multiple myeloma patients, the in vivo cellular interactions required for their differentiation into mature plasma cell tumors remains unclear. Given the extensive interactions of peripheral T cells and normal B cells, we assessed the potential role of T cells in plasma-cell tumor development, by using a myc, raf-containing retrovirus, J3V1, to induce plasmacytomas in normal BALB/c mice, T-cell-deficient nude mice, and T-cellreconstituted nude mice.

Paraproteinemia, plasmacytoma, myeloma and HIV infection

“…Moreover, the follow-up time of these studies is much less than the median of 10 years between detection of paraproteinemia and onset of plasma cell neoplasm seen in the general population. The high concentration, persistent paraproteins reported by Lefrère 68 and others (paraprotein concentrations of 65, 52 64, 67 43 63 and 37 61 g/l have been described) are much more likely to represent pre-malignant states, similar to MGUS in the general population. Conclusive proof, however, must come from long-term follow-up of MGUS-positive AIDS patients who are carefully screened for signs of B lineage neoplasms, particularly plasma cell malignancies.…”

“…T cell dysfunction and depletion in AIDS patients may direct the differentiation of transformed lymphocytes to lymphoma rather than plasma cell malignancy, as T cells are crucial for the induction of plasmacytoma in a mouse model. 43 Although gammopathy, plasmacytoma and myeloma appear to occur far earlier in AIDS patients than in the general population, an increased risk of malignancy in AIDS patients with paraproteins has not been documented. Few patients have been followed long term, and screening for plasma cell neoplasms has not been undertaken.…”

“…In nude mice, a retrovirus containing c-myc and c-raf gives rise to non-immunoglobulin secreting B cell lymphomas, whereas the same retrovirus gives rise to plasmacytomas in both normal mice and nude mice that have had T cell reconstitution. 43 The Abelson murine leukemia virus alone induces a pre-B cell lymphoma, but in combination with the constitutively expressed c-myc, it gives rise to plasmacytomas. 44 These data are consistent with a model in which transformation occurs in B lymphocytes that have undergone somatic hypermutation but are still capable of class switching, and certain stimuli, such as T cell regulation and oncogene expression, are critical in promoting differentiation of the transformed B cells into malignant plasma cells, not lymphoma cells.…”

“…In AIDS patients, the antigenic stimulus is postulated to be not an auto-antigen, but rather the viral proteins of HIV. The induction in nude mice exposed to a transforming virus of plasmacytoma only in the presence of T cells 43 provides a possible explanation for the high frequency of lymphoma compared to myeloma in AIDS patients: the disrupted T cells in AIDS patients may be unable to provide the appropriate stimuli to drive the differentiation of tumorigenic lymphocytes into plasma cells. Thus, multiple mechanisms can account for the early development of MGUS, plasmacytoma, and multiple myeloma in HIV-infected individuals: direct activating effects of the virus on B cells, altered T cell regulation of B cells, infection with EBV, increased levels of IL-6, and chronic exposure to HIV antigens all may contribute to the increased incidence of B lineage neoplasms, while severely deranged T cell function might explain why the vast majority of these lymphocytic malignancies are lymphoma and not plasmacytoma or myeloma.…”

A Rare Case of Multple Myeloma (Mm) Presented With Pancytopaenia in A Patient of HIV – At Very Early Age

“…In addition, the observation that T cells were able to induce terminal differentiation of transformed B cells into mature plasma cell tumours [9] might explain the high frequency of lymphoma as compared to that of myeloma in AIDS patients who were depleted of T cells. In the future, highly active antiretroviral therapy and immune restoration may favour the emergence of plasma cell neoplasms rather than AIDS defining malignancies, the incidence of which has decreased as a consequence of HAART therapy.…”