Functional properties of CD138- and CD138+ cells in Multiple Myeloma: Study in the 5T33MM model

Multiple myeloma (MM) contains a heterogenous mix of tumor cells including CD138- and CD138+ cells. While some studies described that CD138- cells are a minor population containing MM clonogenic and
therapy-resistant cells, others show that only CD138+ cells are able to proliferate and engraft. These studies clearly demonstrate that phenotypical and functional different tumor populations exist, but results are controversial. We investigated CD138- and CD138+ tumor populations in the murine syngeneic 5T33MM model. Both in vitro (clonogenic assay) and in vivo engraftment studies suggest that both populations form colonies and induce MM disease in a syngeneic environment, albeit CD138+ cells more apparent than CD138- cells. Real-time PCR for Blimp-1 and bcl-6 indicate that CD138- cells are less differentiated than CD138+ cells. We investigated in vitro the sensitivity of CD138- and CD138+ cells to drugs (bortezomib (Bz), MG132, melphalan, LBH589, 17AAG) by measuring cell viability and caspase3/7 activation. CD138- cells tend to be more resistant to drugs. Subsequently, we investigated, the phenotype of 5T33MM cells after in vivo treatment with Bz. The percentage of CD138- 5T33MM cells was significantly increased when mice were treated with Bz compared to vehicle. Preliminary results indicate
that CD138- cells express more ABCG2, an ABC transporter involved in resistance. In conclusion, both CD138+ and CD138- cells are important in MM development with the CD138- cells being more therapy resistant indicating that CD138- MM cells should be included in further investigations.