Clinical drug resistance linked to inter-convertible phenotypic and functional states of tumor-propagating cells in multiple myeloma
Menée sur 30 patients atteints d'un myélome multiple, cette étude met én évidence des sous-populations cellulaires impliquées dans la résistance thérapeutique
The phenotype and function of cells enriched in tumor-propagating activity and their relationship to the phenotypic architecture in multiple myeloma (MM) are controversial. Here, in a cohort of 30 patients we show that MM comprises four hierarchically organised, clonally-related sub-populations which, although phenotypically distinct, share the same oncogenic chromosomal abnormalities as well as immunoglobulin heavy chain complementarity region 3 area sequence. Assessed in xenograft assays, myeloma-propagating activity is the exclusive property of a population characterized by its ability for bi-directional transition between the dominant CD19-CD138+ plasma cell (PC) and a low frequency CD19-CD138- subpopulation (termed Pre-PC); in addition, Pre-PC are more quiescent and unlike PC, are primarily localized at extramedullary sites. As shown by gene expression profiling, compared to PC, Pre-PC are enriched in epigenetic regulators, suggesting that epigenetic plasticity underpins the phenotypic diversification of myeloma-propagating cells. Prospective assessment in paired, pre- and post-treatment bone marrow samples shows that Pre-PC are up to 300-fold more drug-resistant than PC. Thus, clinical drug resistance in MM is linked to reversible, bi-directional phenotypic transition of myeloma-propagating cells. These novel biological insights have important clinical implications in relation to assessment of minimal residual disease and development of alternative therapeutic strategies in MM.