Endothelial progenitor cell clonality and response to treatment in multiple myeloma

• Published in: Journal of clinical oncology Vol. 24; no. 18_suppl; p. 17546
• Main Authors: Kahn, D. M., Braunstein, M., Smith, E. L., Klueppelberg, U., Ozcelik, T., Batuman, O.
• Format: Journal Article
• Language: English
• Published: 20.06.2006
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2006.24.18_suppl.17546

Abstract only 17546 Background: In multiple myeloma (MM), increased levels of endothelial progenitor cells (EPCs) contribute to neoangiogenesis, covary with disease activity and response to treatment. To understand the mechanisms of enhanced neoangiogenic function by EPCs in MM, we investigated whether EPCs and tumor cells share clonal identity, and related this finding to clinical progression. EPC clonality was analyzed by X-chromosome inactivation (XCI) and the presence of clonotypic immunoglobulin heavy-chain (IGH) gene rearrangement. Methods: Hair root cells and confluent EPCs from 18 female patients were studied for XCI patterns by human androgen receptor assay (HUMARA). In 6 patients, EPCs were studied for the presence of IGH gene rearrangement using family-specific PCR primers for IGH variable genes (V H ). Nine patients were treated with TDZ: thalidomide (100 mg/day), dexamethasone (10–40 mg for 4 days/3 weeks for 6 months, then reduced to 4 days/month), and zoledronate (4 mg/4 weeks). Results: Eleven of the 18 female patients displayed allelic XCI. Analysis of their EPCs for evidence of clonality revealed significant skewing (≥ 77% expression of a single allele) in 64% (n = 7). In 4 of these 7 patients, EPC XCI skewing was extreme (≥ 90% expression of a single allele) while in hair root cells XCI was random. Furthermore, sequencing of PCR products obtained with V H primers resulted in identification of the same product in EPCs and bone marrow cells in 67% (n = 4) of another 6 patients, while no IGH rearrangement was found in EPCs from healthy controls. 9 patients were subsequently treated with TDZ, 4 patients had clonal EPCs and Stage 2 MM, and 5 patients had non-clonal EPCs and Stage 3 MM. Despite having less advanced disease, patients whose EPCs were clonal had a significantly attenuated response to treatment with TDZ compared to patients whose EPCs were non-clonal (P = .05). Conclusions: Clonal identity between EPCs and neoplastic cells highlight the necessity to explore the thesis that MM cells and EPCs are derived from a progenitor cell capable of self-renewal and differentiation. The relationship between EPC clonality and impaired response to treatment underscores the pathogenic significance of EPCs in MM. No significant financial relationships to disclose.