The bone marrow of multiple myeloma patients contains B cell populations at different stages of differentiation that are clonally related to the malignant plasma cell.

Abstract

Suml-nal'~One of the distinguishing features of multiple myeloma (MM) is the proliferation of a clonal plasma cell population in the bone marrow (BM). It is of particular interest that the tumor plasma cells appear to be restricted to the microenvironment of the BM and are rarely detected in the peripheral system, yet the disease is found widely disseminated throughout the axial skeleton. Furthermore, isolation of MM tumor cell lines has proven to be quite problematic due to their slow growth rate. These observations have instigated the search for earlier cells in the B cell lineage that are clonally related to the plasma cell tumor and that may represent the growth fraction of the tumor. We used allele-specific oligonucleotides (ASO) derived from the third complementarity determining region of the rearranged tumor immunoglobulin heavy chain gene to detect isotypes clonally related to the plasma cell tumor. By reverse transcribing RNA from the BM with a panel of CH primers (/~, 8, o~, and 30, followed by ASO-polymerase chain reaction amplification, we demonstrate the existence of preswitch isotype species that are clonally related to the myeloma tumor. Furthermore, we show that separation of the BM cells into CD45 + and CD38 § cell populations results in a lineage-specific expression of the donally related RNA molecules, with the C/~ and C8 in the CD45 § and C3~ in the CD38 § population. Interestingly, clonally related Co~ transcripts are also derived from the CD45 + fraction. These results confirm the presence of B cell populations clonally related to the plasma cell tumor and are consistent with models that propose the existence of myeloma precursors.

Paraproteinemia, plasmacytoma, myeloma and HIV infection

“…21 Recent investigations have begun to elucidate from where in the B cell lineage the malignant myeloma clones originate. 27 On the basis of immunoglobulin and other gene sequences, B lymphocytes clonally related to malignant plasma cells have been identified in the bone marrow [28][29][30][31] and peripheral blood 28,30,[32][33][34][35][36][37] of myeloma patients. Myeloma cells, as well as these clonally related lymphocytes, express immunoglobulin genes that have undergone somatic hyper-mutation, reflecting antigen exposure.…”

“…Myeloma cells, as well as these clonally related lymphocytes, express immunoglobulin genes that have undergone somatic hyper-mutation, reflecting antigen exposure. 27,30,31,36,38,39 Ongoing hypermutation does not occur during tumor progression. 39 Thus, transformation occurs after somatic hypermutation, and the lack of subsequent mutation indicates that the malignant, clonal lymphocyte-plasma cell population has escaped the antigen selection process.…”

“…39 Thus, transformation occurs after somatic hypermutation, and the lack of subsequent mutation indicates that the malignant, clonal lymphocyte-plasma cell population has escaped the antigen selection process. Lymphocyte populations clonally related to myeloma cells undergo class switching, 30,31,36,41 indicating that transformation occurs prior to class switching and leaves intact either the switching mechanisms or a preprogrammed switch. The transformed population in myeloma thus appears to be restricted to the myelomatous plasma cells and clonally related, hypermutated, pre-switched B lymphocyte populations found in the bone marrow or periphery.…”

The peripheral CD138+ population but not the CD138− population contains myeloma clonogenic cells in plasma cell leukaemia patients

“…The B-cell nature of myeloma 'stem' cells was addressed when it was shown that myeloma-related clonotypic B cells exist in patients with MM (Billadeau et al, 1993;Rasmussen et al, 2004). It is well known that memory B-cells are biased toward plasma cells: once memory B cells are activated, they enter the cell cycle, and most begin differentiation into plasmablasts and then plasma cells, while some exit the cell cycle and remain at the B-cell stage (Jégo et al, 2001).…”

CD34+ selection of autologous peripheral blood stem cells for transplantation following sequential cycles of high-dose therapy and mobilisation in multiple myeloma

“…5,6 Clonotypic B cells have been demonstrated in autologous blood/bone marrow stem cells in MM [7][8][9][10][11] and a correlation between autografting with heavily contaminated material and relapse has been suggested in MM and other diseases. 9,12 Purging of transplant material to reduce malignant contamination may involve treatment of patients either by radiation, chemical or immunological means prior to collection of autologous cells in order to achieve an in vivo purging effect.…”