**Acknowledgements**

Series of experiments have demonstrated that hypoxia is responsible for altering the cellular phenotype by causing an increase in proliferation, self-renewal and upregulation of stem cell genes in both CSC and non-CSC. Several groups have shown that hypoxia can regulate histone methylation and thus alter the epigenetic status of cancer cells [140-142]. Tumor hypoxia also correlates with poor outcome of patients. HIFs were shown to induce the embryonal stem celllike transcriptional program, including *OCT4, NANOG, SOX2, KLF4, MYC*, and micro‐ RNA-302 in cancer cell lines of prostate, brain, kidney, cervix, lung, colon, liver and breast tumors [143]. Hypoxic microenvironment potentiates biological effect of Notch signaling in adenocarcinoma of the lung or alters gene expression of neuroblastoma cells to induce more immature phenotype [144, 145]. CD133, a cancer stem cell marker, has been reported by several groups to be upregulated under hypoxic conditions [146, 147]. McCord et al. [2009] showed that hypoxia not only increased the sub-population of glioblastoma cells positive for CD133, but also enhanced expression of other stem cell markers, such as SOX2, OCT4 and nestin [148]. Low oxygen levels induced also HIF-2α expression that can increase the expression of stem

The BM microenvironment of MM is also hypoxic, and myeloma PCs are long term exposed to low oxygen levels. Tumor adaptation to hypoxia is mediated by the production of HIF-1 [149]. Both HIF-1α and HIF-2α have been reported to be activated in MM patients resulting in stimulation of angiogenesis [150]. Although a role of BM microenvironment is generally recognized as a crucial factor affecting myeloma development and support progression, it is surprising that an importance of hypoxic microenvironment for modulation of plasma cell

Despite the achievements of currently used therapy, MM remains difficult to treat. Novel agents such as inhibitors of proteasome or immunomodulatory drugs have prolonged survival of patients with MM and even some patients persist in long term remission. However, there is a little known about mechanisms of myeloma development or the population responsible for the origin and relapse of the disease. Many scientists have tried to explain causes of the relapse but none of their theories have been conclusively confirmed so far. In this review, we explain inconsistencies among particular concepts and the inability to detect cells of origin by the plasticity potential of myeloma PCs. Plasticity of myeloma PCs might be a cause of vast phenotypic heterogeneity of MM and different characteristics of putative myeloma precursors. Under specific signals from aberrant microenvironments, PCs might undergo dedifferentia‐ tion/transdifferentiation changing their phenotype profile, and acquire stem cell-like proper‐ ties to ensure survival. Therefore, an effort to target the specific cell type based only on surface markers is not sufficient. Instead, it is necessary to concentrate on pathologic mechanisms responsible for the transition from non-CSC to CSC like cells. Additional focus on adjacent microenvironments and specific prevention of stem cell-like conversion might increase success

cell-associated genes and confer tumorigenic potential to non-CSC [140].

phenotype have never been studied in MM.

78 Multiple Myeloma - A Quick Reflection on the Fast Progress

**7. Conclusion**

of future therapy.

This work was supported by grants from The Ministry of Education, Youth and Sports: MSM0021622434 and Czech Science Foundation GAP304/10/1395. The authors would like to thank Andrea Knight for proof reading the manuscript.
