labelling index and remain quiescent except in end-stage 
myeloma. Instead, the primary malignant event is 
hypothesized to occur in an earlier pro-B or pre-B cell, 
possibly in a lymph node or extra-nodal lymphatic tissue. 8 
Progeny of this myeloma "stem cell", identifiable only by 
clonal immunoglobulin gene rearrangement, may then migrate 
via the circulation to the bone marrow, where release from 
normal regulatory constraints could occur. 3,9 Murine 
plasmacytomas have been shown to have consistent cytogenetic 
abnormalities involving dysregulation of the c-myc oncogene 8 
but human myelomas have not yet been found to exhibit 
uniform cytogenetic abnormalities or mutations activating 
oncogenes. ‘° 
Over the past several years, interest has been focused on 
interleukin-6 as a growth factor for myeloma cells. 1 In 
several murine model systems dysregulated IL-6 production 
can lead to abnormal plasma cell proliferations resembling 
human myeloma or other plasmacytic tumors such as the giant 
lymph nodes described in Castleman's Disease. 11,12 Murine 
plasmacytoma cell lines deprived of IL-6 undergo 
apoptosis . (R.Norden, personal communication) In human 
myeloma cell lines and fresh myelomatous marrow samples, 
initial observations suggested that IL-6 was an autocrine 
stimulatory factor produced by myeloma tumor cells 
themselves 13 , but more recent data instead supports the - 
concept that in early disease, accessory cell or marrow 
stromal overproduction of IL-6 is more important. 1,9,14 High 
circulating levels of IL-6 have been associated with poor- 
prognosis myeloma. 15,16 A recent case report from France 
described treatment of a patient with plasma cell leukemia 
with anti-interleukin-6 antibodies, with some response. 17 
The co-existence of myeloma cells with normal bone marrow 
precursors in a stromal environment where excess 
interleukin-6 production or other dysregulated 
microenvironmental, ^influences can act suggests to us that 
hematopoietic stem cell-targeted gene therapy might in the 
future be a possible therapeutic approach to multiple 
myeloma. Paracrine or autocrine loops could be interrupted 
by high concentrations of inhibitors delivered directly to 
the marrow microenvironment. Possible therapeutic agents 
that could be delivered in this manner include alpha- 
interferon, soluble IL-6 receptor, -soluble gpl30 (the non- 
ligand-binding component of the high-affinity IL-6 receptor) 
or ah IL-6 receptor antagonist. 
Recombinant DNA Research, Volume 16 
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