in-vitro-differentiation-model-human-normal-memory-b-cells-to-long

In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells

Plasma cells (PCs) secrete large amounts of antibodies and develop from B cells that have been activated. PCs are rare cells located in the bone marrow or ...

Univ Montpellier

Multiple myeloma (MM) is the second most common hematologic malignancy. Aberrant epigenetic modifications have been reported in MM and could be promising therapeutic targets. As response rates are overall limited but deep responses occur, it is important to identify those patients who could indeed benefit from epigenetic-targeted therapy.

DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells.

Multiple myeloma (MM) is a malignant plasma cell disease with a poor survival, characterized by the accumulation of myeloma cells (MMCs) within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance.

PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs.

Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated plasma cells, which are predominantly localized in the bone marrow. Myeloid-derived suppressor cells (MDSC) are described to promote MM progression by immunosuppression and induction of angiogenesis. However, their direct role in drug resistance and tumor survival is still unknown. In this study, we performed co-culture experiments of myeloma cells with 5TMM derived MDSC in vitro, leading to increased survival and proliferation of MM cells. Co-culture experiments resulted in MDSC-induced AMPK phosphorylation in MM cells, which was associated with an increase in the anti-apoptotic factors MCL-1 and BCL-2, and the autophagy-marker LC3II. In addition, 5TMM cells inoculated in mice showed a clear upregulation of AMPK phosphorylation in vivo. Targeting the AMPK pathway by Compound C resulted in apoptosis of human myeloma cell lines, primary MM cells and 5TMM cells. Importantly, we observed that the tumor-promoting effect of MDSC was partially mediated by AMPK activation. In conclusion, our data clearly demonstrate that MDSC directly increase the survival of MM cells, partially through AMPK activation, identifying this pathway as a new target in the treatment of MM patients.

Article	Year
DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells. British journal of cancer\| PubMed ID: 29500406	2018
PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs. Clinical epigenetics\| PubMed ID: 30285865	2018
Myeloid-derived suppressor cells induce multiple myeloma cell survival by activating the AMPK pathway. Cancer letters\| PubMed ID: 30419344	2019

Alboukadel Kassambara

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