Blood, 15 August 2002, Vol. 100, No. 4, pp. 1109-1109
New technologies in the myeloma gene mine
The new gene expression profiling technologies are
redefining malignancy. In a previous article published in Blood
(2002;99:1745-1757), Dr Shaughnessy's group published gene expression
profiles of malignant plasma cells and included comparisons with normal
plasma cells that were arduously sorted from normal tissues. In a
report here, Tarte et al (page 1113) approach the limitation of
obtaining normal plasma cells by developing a method to differentiate
normal peripheral blood B cells to polyclonal plasmablastic cell
populations. They demonstrate with extensive genetic and phenotypic
characterizations that normal polyclonal plasma cells can be obtained
not only from healthy volunteers but also from the myeloma patients.
This provides a novel gene profile comparison of malignant and normal
plasma cells from the individual patient, thus reducing population
heterogeneity that can confound normal versus malignant profiles. By
including data from the Shaughnessy studies these authors demonstrate
gene expression patterns of the in vitro-generated polyclonal
plasmablasts are very similar to those of bone marrow- derived plasma
cells. Thus, this approach provides both comparison of normal and
malignant cells gene profiles and also a powerful tool to identify
genes involved in plasma cell differentiation.
The approach was validated by the differential expression of genes
known to be restricted in the various cell populations. From these
studies the authors conclude that (1) there is no intrinsic defect of
the nonmalignant B cells from MM patients to differentiate into plasma
cells, (2) the model described may allow identification of gene
expression alterations involved in MM pathogenesis, and (3) an in vitro
differentiation model may be useful to investigate, using gene
transfer, the role of deregulated genes to transform normal cells to
malignant ones. The true effort comes in identifying the functional
relevance of sets of genes that distinguish stages of development in
normal cells versus malignant plasma cells. Of 50 myeloma-specific
genes, 5 cancer/testis tumor antigen genes were noted in a subset and
represent potential tumor-specific therapeutic targets. One
limitation of such studies is the nagging concern that the true
transformed cell progenitor in myeloma may be derived from B cells
earlier in differentiation than the plasma cell, and until that
controversy is resolved, the exact relevant pairs of comparisons that
may identify critical myeloma-specific genes may have to be carefully
considered. Moreover, there is likely a complex interplay in
intracellular communication, and the challenge is to attribute
functional consequences of the patterns identified. With that comes not
only an understanding of the disease but additional potential
therapeutic targets. The current report by Tarte et al provides another
step in technical development to produce and mine the data.
Brian Van Ness
University of
Minnesota
