Abstract
Gene expression-based scores used to predict risk in cancer frequently include genes coding for DNA replication, repair or recombination. Using two independent cohorts of 206 and 345 previously-untreated patients with Multiple Myeloma (MM), we identified 50 cell cycle-unrelated genes overexpressed in multiple myeloma cells (MMCs) compared to normal human proliferating plasmablasts and non-proliferating bone marrow plasma cells and which have prognostic value for overall survival. Thirty-seven of these 50 myeloma genes (74%) were enriched in genes overexpressed in one of 3 normal human stem cell populations – pluripotent (18), hematopoietic (10) or mesenchymal stem cells (9) - and only three genes were enriched in one of 5 populations of differentiated cells (memory B lymphocytes, T lymphocytes, polymorphonuclear cells, monocytes, osteoclasts). These 37 genes shared by MMCs and adult or pluripotent stem cells were used to build a stem cell score (SCscore), which proved to be strongly prognostic in the 2 independent cohorts of patients compared to other gene expression-based risk scores or usual clinical scores using multivariate Cox analysis. This finding highlights cell cycle-unrelated prognostic genes shared by myeloma cells and normal stem cells, whose products might be important for normal and malignant stem cell biology.
Highlights
Multiple Myeloma (MM) is a molecularly heterogeneous disease with recurrent gene translocations, deletions or gains and changes in gene expression in Multiple Myeloma Cells (MMCs) [1,2]
We and others have shown that 3 of 4 Yamanaka genes – KLF4, SOX2 and MYC - are expressed by MMCs [12], suggesting MMCs could dedifferentiation in vivo
Preplasmablasts and plasmablasts were used to delete genes coding for cell cycle machinery. 885 unique probe sets, coding for 678 unique myeloma genes or ESTs were overexpressed in primary MMCs (281 probe sets) or in HMCLs (702 probe sets) compared to normal counterparts (Supplementary Table S2)
Summary
Multiple Myeloma (MM) is a molecularly heterogeneous disease with recurrent gene translocations, deletions or gains and changes in gene expression in Multiple Myeloma Cells (MMCs) [1,2]. High throughput DNA microarrays made it possible to identify geneexpression in MMCs linked with event free and/or overall survival of previously-untreated patients These includes the high risk score from the University for Medical Sciences of Arkansas (UAMSHRS) [3], the intergroupe Francophone du Myelome (IFM) score [4], and surrogate markers of proliferation [5,6]. Several studies have emphasized the existence of a Myeloma Stem cell, which lacked CD138, was able to form colonies in semi-solid medium in vitro, and recapitulate the tumor growth in vivo [8]. These studies were not confirmed, weakening the stem cell hypothesis in Multiple Myeloma [9]. We and others have shown that 3 of 4 Yamanaka genes – KLF4, SOX2 and MYC - are expressed by MMCs [12], suggesting MMCs could dedifferentiation in vivo
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