Authors: Naoki Hosen
Publish Date: 2013/02/19
Volume: 97, Issue: 3, Pages: 306-312
Abstract
Multiple myeloma MM is characterized by the clonal expansion of malignant plasma cells As in other cancers MM plasma cells are thought to be derived from MMinitiating cells although these remain unidentified MM patients harbor phenotypic CD19+ B cells expressing the immunoglobulin gene sequence and the idiotype unique to the individual myeloma clone Some previous studies have reported that CD19+ clonotypic B cells can serve as MMinitiating cells However we and another group have recently showed that CD19+ B cells from many MM patients do not reconstitute MM disease upon transplantation into NOD/SCID IL2Rγc−/− mice In the SCIDrab and SCIDhu models which enable engraftment of human MM in vivo CD19−CD38++ plasma cells engrafted and rapidly propagated MM while engraftment of CD19+ B cells was not detected Both CD138− and CD138+ plasma cells have the potential to propagate MM clones in vivo in the absence of CD19+ B cells Distinct from acute myeloid leukemiainitiating cells which are derived from undifferentiated stem or progenitor cells MMinitiating cells are derived from plasma cells which are terminally differentiated cells An improved understanding of how the bone marrow microenvironment supports MMinitiating plasma cells which can initiate MM disease in the SCIDhu or rab model is thus now essentialMMinitiating cells originate from postgerminal center B cells Differentiation steps from hematopoietic stem cells to plasma cells are shown VDJ recombination and somatic hypermutations produce the varieties in immunoglobulin sequences IgH VDJ sequences of MM plasma cells contain somatic hypermutation but no clonal variation indicating that postgerminal center B cells are the origin of MMinitiating cellsCD19+ B cells isolated from MM patients could reportedly generate MM disease upon transplantation into NOD/SCID mice in a few MM patients 11 12 13 14 indicating that clonotypic CD19+ B cells served as MM progenitor cells in these patients These results suggested that CD19+ clonotypic B cells are important therapeutic targets in MM therapy However B cell depletion by means of rituximab in MM patients was not clinically effective in most cases at least for short periods 15 It is therefore still unclear whether CD19+ or CD20+ clonogenic MM progenitor cells are responsible for disease progression and maintenanceCD19+ B cells from MM samples did engraft and initiate MM disease in NOG mice a FACS analysis of BM cells of NOG mice transplanted with CD19+ B cells from the patient’s BM Corresponding data for an NOG mouse transplanted with cord bloodderived CD34+ cells is shown for reference Analyses were performed 12 weeks posttransplant b FACS analysis findings of NOG mice transplanted with CD3− BM cells from a MM patient sample 12 weeks after transplant Expression of cytoplasmic IgLκ and λ in CD38++CD138+ cells was also analyzed to determine whether they were clonal MM cellsTaken together the presence of CD19+ MMinitiating cells could not be proven by xenotransplant assay using NOG mice as recipients in many of MM patients although it is certain that there are small numbers of MM cases in which CD19+ B cells has MMinitiating potential as previously reportedSCIDhu or SCIDrab model has been used for reconstitution of MM disease in mice 18 19 In Japan only SCIDrab model is permitted to perform A human or rabbit bone fragment is inserted under the skin of a SCID mouse more than 4 weeks before transplantation of MM cells Samples from MM patients are injected into the human or rabbit bone and the engraftment and expansion of MM cells can be detected by measuring human immunoglobulin light chain IgL κ and λ in serum of the recipient mouse We first transplanted whole BM cells from MM patients and engraftment of MM cells was monitored by measuring human IgLκ and λ in serum of the recipient mice Engraftment and expansion of MM cells were observed in 5 out of 12 cases Rabbit BM was analyzed 12 weeks or more after transplant to determine whether engraftment of not only MM plasma cells but also CD19+ B cells had taken place Robust engraftment of human CD38++ MM plasma cells expressing the monotypic immunoglobulin light chain and containing both CD138− and CD138+ cells was detected in the rabbit BM but no human CD19+ B cells were detected These results indicate that CD19−CD38++ plasma cells could engraft and expand at least for several months without engraftment of CD19+ B cells The same results have been recently reported using SCIDhu system by Kim and Weissman 17Both CD138− and CD138+ plasma cells but not CD19+ B cells could engraft and propagate MM clones in the SCIDrab model Transplantation of purified CD138−CD34− or CD138+ cells from MM BM cells into SCIDrab recipients Concentration of human IgL in serum at 12 weeks posttransplant and the results of analysis of BM cells at 12 weeks CD138− or 24 weeks CD138+ are shown
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