学会賞| Award
The 10th JSH International Symposium 2019 in Ise-Shima

17th EHA Congress Travel Award 受賞レポート 奈良 美保



名前:奈良 美保【秋田大学大学院医学研究科 血液・腎臓・膠原病内科学分野】


Identification of therapeutic candidate targets specifically expressed in myeloma side population cells


Background: Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow. Cytotoxic chemotherapy-based treatment is not curative, however, and the disease eventually recurs. Although currently available anti-MM strategies are effective at targeting the bulk of tumor cells, it is not clear that these agents are targeting the tumor-initiating subpopulation, or cancer stem cells. Side Population (SP) cells express high levels of various members of the ABC transporter family, which are responsible for their drug resistance. A recent work by Jakubikova et al (Blood, 2011) demonstrated that SP cells in MM have shown to exhibit stem cell like characteristics as well as high tumorigenicity.

Aims: The aim of our study is to identify gene/proteins specifically expressed in myeloma SP cells, which could be essential therapeutic targets.

Methods: We isolated SP cells from MM cell lines by use of Hechest 33342 dye to examine potential of tumorigenicity (transplantation SP cells into NOD/Shi-scid IL-2γnul mice).Gene expression analysis of SP and non-SP cells were performed against 5 MM cell lines and 8 primary samples.Aurora kinase inhibitor (VX-680), 3-deazaneplanocin A(DZNep), and a proteasome inhibitor, bortezomib were exposed to RPMI 8226 and AMO1.

Results: We found that myeloma SP cells expressing CD138 exhibit greater tumorigenetic potential than non SP cells.  Gene expression analysis of 5 cell lines and CD138-positive primary samples revealed that, in SP cells, expression of cell cycle (e.g. CCNB1)-, microtubule attachment (e.g. BIRC5)-, mitosis or centrosome (e.g. AURKB)-, proliferation (e.g. TOP2A)-, polycomb (e.g. EPC1, EZH2)- and ubiquitin-proteasome (e.g.PSMA5)- geneswas significantly stronger than in non-SP cells.On that basis, we used an aurora kinase inhibitor (VX-680 for AURKB), histone methylation inhibitor (DZNep for EZH2) and a proteasome inhibitor (bortezomib for S20/S26 proteasomes) against RPMI 8226 and AMO1.Of these, bortezomib reduced the SP fraction more effectively than the other agents due to its ability to reduce levels of phospho-histone H3, EZH2 and PSMA5.This suggests bortezomib has a greater range of targets than other agents and could include cell cycle, centrosome, polycomb and proteasome genes/proteins.

Conclusions: We found that myeloma SP cells exhibit strong tumorigenicity in vivo, and showed that they more strongly express cell cycle (G2/M)-, centrosome-, polycomb- and ubiquitin-proteasome-related genes than non-SP cells. We also demonstrated that reducing transcription of all these genes is necessary when targeting myeloma SP cells, and that bortezomib is capable of shrinking the myeloma SP by downregulating the aforementioned genes.Our approach could be useful for screening new agents with which to target a population possessing strong tumor initiating potential in MM.

EHA congress 印象記:

ポスター発表風景  この度は2012年6月14日から17日までオランダで開催された、The 17th EHA congressに参加する機会を与えて下さり誠にありがとうございました。

 EHA日程は、初日のスポンサー企業によるSatellite symposia、2日目以降にはEducation session、Simultaneous session、Plenary session、Poster sessionなどが開催されました。私の印象では、ASHよりもプログラム構成に余裕があり、Education sessionも午前と午後とで2回催されるため、自分の興味あるsessionのすべてを聴講することができました。また、会場もASHほどは広くなく、次のsessionへの移動も楽で、余裕をもって過ごすことができ、EHAは有意義なものとなりました。

 特に、Molecular Hemopoiesis Workshopのstem cell sessionでは、stem cell研究の最新の話題、また私の研究テーマであるmyelomaのSimultaneous sessionでは、臨床研究に基礎分野を取り入れたデータ解析を勉強させていただきました。  
  私のポスター発表では、国外の先生と1対1でdiscussionができ、最後には「nice study !」と言っていただくと、お世辞とわかっていながらも大変うれしく感じました。


  このようなご機会を賜りました、日本血液学会 事務局、国際委員会の方々に深くお礼申し上げます。


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