Figure 4
Figure 4. Myeloma-propagating potential of Pre-PCs and PCs and partial recapitulation of the clonotypic hierarchy in NSG mice. (A) Left: Highly purified BM CD138hi myeloma PCs transferred to NSG mice engraft murine BM, spleen, and liver. Human cells are identified in mouse tissues by flow cytomtery as hCD59+mCD45.1− (top panels). Engrafted PCs recapitulate the CD19− hierarchy of the human BM (bottom panels); however, in the spleen and liver, there is preferential presence of Pre-PCs and CD138low cells. Right: BM hematoxylin and eosin staining in a mouse transplanted with CD138hi PC shows myeloma cell infiltration. Immunohistochemistry (original magnification ×400) for human κ/λ light chains and CD138 is also shown. In this example, myeloma PCs are κ LC restricted and, as expected, express CD138. (B) Cumulative data of the frequencies of PCs, CD138low, and Pre-PCs in the BM, spleen, and liver in mice receiving patient CD138hi PCs. Horizontal lines indicate median values. (C) Size of BM PCs and Pre-PCs highly purified by flow sorting from the BM of mice engrafted after transfer of CD138hi myeloma PCs. A representative example is shown. (D) Cell cycle analysis in multiparameter flow cytometry of engrafted BM Pre-PCs and PCs. (E) Engraftment pattern in the murine BM after transfer of Pre-PCs recapitulates Pre-PC–PC duality. Pre-PCs were negatively selected by flow sorting as Lin−CD19−CD34−CD138− cells. In this example, 13.4% of the flow-sorted cells were clonotypic as assessed by quantitative PCR and a total of 33.5 × 103 clonotypic B cells were infused. (F) PB and BM clonotypic cell dynamics in the timeline of treatment of a patient with MM (ASCT indicates autologous stem cell transplantation; and Bort/Dex: bortezomib and dexamethasone) and disease status changes (MolR indicaets molecular remission; IF, immunofixation; and CR, complete clinical remission). Blood clonotypic CD19+ cells, Pre-PCs, and CD138low cells, but not PCs, are identified while the patient was in complete clinical and molecular remission in the BM at 5.6 and 11.1 months.

Myeloma-propagating potential of Pre-PCs and PCs and partial recapitulation of the clonotypic hierarchy in NSG mice. (A) Left: Highly purified BM CD138hi myeloma PCs transferred to NSG mice engraft murine BM, spleen, and liver. Human cells are identified in mouse tissues by flow cytomtery as hCD59+mCD45.1− (top panels). Engrafted PCs recapitulate the CD19− hierarchy of the human BM (bottom panels); however, in the spleen and liver, there is preferential presence of Pre-PCs and CD138low cells. Right: BM hematoxylin and eosin staining in a mouse transplanted with CD138hi PC shows myeloma cell infiltration. Immunohistochemistry (original magnification ×400) for human κ/λ light chains and CD138 is also shown. In this example, myeloma PCs are κ LC restricted and, as expected, express CD138. (B) Cumulative data of the frequencies of PCs, CD138low, and Pre-PCs in the BM, spleen, and liver in mice receiving patient CD138hi PCs. Horizontal lines indicate median values. (C) Size of BM PCs and Pre-PCs highly purified by flow sorting from the BM of mice engrafted after transfer of CD138hi myeloma PCs. A representative example is shown. (D) Cell cycle analysis in multiparameter flow cytometry of engrafted BM Pre-PCs and PCs. (E) Engraftment pattern in the murine BM after transfer of Pre-PCs recapitulates Pre-PC–PC duality. Pre-PCs were negatively selected by flow sorting as Lin−CD19−CD34−CD138− cells. In this example, 13.4% of the flow-sorted cells were clonotypic as assessed by quantitative PCR and a total of 33.5 × 103 clonotypic B cells were infused. (F) PB and BM clonotypic cell dynamics in the timeline of treatment of a patient with MM (ASCT indicates autologous stem cell transplantation; and Bort/Dex: bortezomib and dexamethasone) and disease status changes (MolR indicaets molecular remission; IF, immunofixation; and CR, complete clinical remission). Blood clonotypic CD19+ cells, Pre-PCs, and CD138low cells, but not PCs, are identified while the patient was in complete clinical and molecular remission in the BM at 5.6 and 11.1 months.

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