Elucidation of the mechanisms of extramedullary disease development and drug resistance in multiple myeloma.

• Project/Area Number: 20K08761
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Kikuchi Jiro 自治医科大学, 医学部, 准教授 (60371035)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 多発性骨髄腫 / 髄外増幅 / 薬剤耐性 / CD44 / 細胞間相互作用

Outline of Research at the Start

多発性骨髄腫は現在も約40％が６年以内に死亡する難治性の造血器腫瘍である。病態の進展に伴い骨髄腫細胞が肝臓・軟部組織などに転移し細胞塊を形成しながら増殖する髄外増幅が発生、治療抵抗性となり予後が悪化する。細胞塊形成に伴う骨髄腫細胞間の相互作用が薬剤耐性獲得に働くと推測されるがその機序は未解明である。本研究では、細胞塊形成機序の解明から髄外増幅を発症するマウスモデルを樹立、続いて薬剤耐性獲得機構の解明から髄外増幅の予防や除去に有効な治療法の開発を目指す。

Outline of Final Research Achievements

Elucidating the mechanism of extramedullary disease (EMD) development would contribute to improvement of treatment outcome in patients with MM. Here, we show that bone marrow stroma cell-derived hyaluronan (HA) elicits homophilic interactions of MM cells by binding to surface CD44 variants, under physiological shear stress and generates cell clusters that might develop into EMD. We recapitulated the development of EMD via administration of HA in a syngeneic murine MM model in a CD44-dependent manner. HA-induced MM cell clusters exhibited the specific resistance to proteasome inhibitors (PIs) via γ-secretase-mediated cleavage of the intracellular domains of CD44, which in turn transactivated PI resistance-inducible genes. Anti-CD44 antibody or γ-secretase inhibitors readily suppressed the development of EMD and significantly prolonged the survival of recipients. The HA-CD44 axis represents a novel pathway to trigger EMD development and could be a target of the treatment of EMD.

Academic Significance and Societal Importance of the Research Achievements

申請者が見出したシェアストレス下における骨髄腫細胞塊の形成は前例のない独自のモデルである。このモデルにより骨髄腫細胞同士の相互作用の役割や、薬剤耐性獲得における新たな機序解明の進展が期待できるなど、本研究には極めて高い学術的独創性が示唆される。また、髄外増幅発症と薬剤耐性獲得機序の解明は、その予防や克服に有効な新規治療法の開発を介して予後を改善する効果が期待できる。

Research Products

• [Journal Article] EMD originates from hyaluronan-induced homophilic interactions of CD44 variant-expressing MM cells under shear stress (2023)
  • Author(s): Jiro Kikuchi, Nobuyuki Kodama, Masataka Takeshita, Sho Ikeda, Takahiro Kobayashi, Yoshiaki Kuroda, Michihiro Uchiyama, Naoki Osada, Bjarne Bogen, Hiroshi Yasui, Naoto Takahashi, Akiyoshi Miwa, Yusuke Furukawa
  • Journal Title: Blood Adv Volume: 7 Issue: 4 Pages: 508-524
  • DOI: 10.1182/bloodadvances.2022007291
  • Peer Reviewed / Open Access
• [Journal Article] Fast in-vitro screening of FLT3-ITD inhibitors using silkworm-baculovirus protein expression system (2022)
  • Author(s): Naoki Yamamoto, Jiro Kikuchi, Yusuke Furukawa, Naoya Shibayama
  • Journal Title: PLoS One Volume: 17 Issue: 5 Pages: e0261699-e0261699
  • DOI: 10.1371/journal.pone.0261699
  • Peer Reviewed / Open Access
• [Journal Article] Autophagic degradation of NOXA underlies stromal cell-mediated resistance to proteasome inhibitors in mantle cell lymphoma (2021)
  • Author(s): Kuroda Y, Koyama D, Kikuchi J, Mori S, Ichinohe T, Furukawa Y.
  • Journal Title: Leukemia research Volume: 111 Pages: 106672-106672
  • DOI: 10.1016/j.leukres.2021.106672
  • Peer Reviewed
• [Journal Article] mTOR inhibitors sensitize multiple myeloma cells to venetoclax via IKZF3-and Blimp-1-mediated BCL-2 up-regulation (2021)
  • Author(s): Naoki Osada, Jiro Kikuchi, Daisuke Koyama, Yoshiaki Kuroda, Hiroshi Yasui, Joel D Leverson, Yusuke Furukawa
  • Journal Title: Haematologica Volume: 106 Issue: 11 Pages: 3008-3013
  • DOI: 10.3324/haematol.2021.278506
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A suitable anti-myeloma drug to overcome drug resistance in bone marrow microenvironment. (2021)
  • Author(s): Kikuchi Jiro, Osada Naoki, Furukawa Yusuke.
  • Journal Title: International Journal of Myeloma Volume: 11 Pages: 7-9
  • Peer Reviewed
• [Journal Article] Bone marrow stromal cell-mediated degradation of CD20 leads to primary rituximab resistance in mantle cell lymphoma (2020)
  • Author(s): Kuroda Yoshiaki、Yashima-Abo Akiko、Koyama Daisuke、Kikuchi Jiro、Mori Shigehisa、Ito Shigeki、Furukawa Yusuke
  • Journal Title: Leukemia Volume: in press Issue: 5 Pages: 1506-1510
  • DOI: 10.1038/s41375-020-01035-x
  • Peer Reviewed / Open Access
• [Journal Article] AMP‐activated protein kinase activation primes cytoplasmic translocation and autophagic degradation of the BCR‐ABL protein in CML cells (2020)
  • Author(s): Koyama Daisuke、Kikuchi Jiro、Kuroda Yoshiaki、Ohta Masatsugu、Furukawa Yusuke
  • Journal Title: Cancer Science Volume: 112 Issue: 1 Pages: 194-204
  • DOI: 10.1111/cas.14698
  • Peer Reviewed / Open Access
• [Journal Article] Molecular basis of clonal evolution in multiple myeloma (2020)
  • Author(s): Furukawa Yusuke、Kikuchi Jiro
  • Journal Title: International Journal of Hematology Volume: 111 Issue: 4 Pages: 496-511
  • DOI: 10.1007/s12185-020-02829-6
  • Peer Reviewed
• [Journal Article] Soluble SLAMF7 Promotes the Growth of Myeloma Cells via Homophilic Interaction with Surface SLAMF7. (2020)
  • Author(s): Kikuchi J, Hori M, Iha H, Toyama-Sorimachi N, Hagiwara S, Kuroda Y, Koyama D, Izumi T, Yasui H, Suzuki A, Furukawa Y.
  • Journal Title: Leukemia. Volume: 34 Issue: 1 Pages: 180-195
  • DOI: 10.1038/s41375-019-0525-6
  • Peer Reviewed / Open Access
• [Journal Article] Kinetics of cytokine receptor internalization under steady-state conditions affects growth of neighboring blood cells. (2019)
  • Author(s): Nagamachi A, Kikuchi J, Kanai A, Furukawa Y, Inaba T.
  • Journal Title: Haematologica Volume: in press Issue: 7 Pages: 1-14
  • DOI: 10.3324/haematol.2019.232959
  • Peer Reviewed / Open Access
• [Presentation] Extramedullary diseases originate from hyaluronan-induced homophilic cell-cell interaction of myeloma cells. (2022)
  • Author(s): Jiro Kikuchi, Nobuyuki Kodama, Masataka Takeshita, Tomoko Hishima, Sho Ikeda, Takahiro Kobayashi, Yoshiaki Kuroda, Michihiro Uchiyama, Naoki Osada, Bjarne Bogen, Hiroshi Yasui, Naoto Takahashi, Akiyoshi Miwa, Yusuke Furukawa
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] c-FOS mediates IMiDs resistance by acting as a co-activator of IKZF1-target genes in multiple myeloma (2022)
  • Author(s): Naoki Osada, Jiro Kikuchi, Hiroshi Yasui, Yusuke Furukawa
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] c-FOS mediates IMiDs resistance acting as a co-activator of IKZF1-target genes in multiple myeloma. (2022)
  • Author(s): Naoki Osada, Jiro Kikuchi, Hiroshi Yasui, Sho Ikeda, and Yusuke Furukawa
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Extramedullary diseases originate from hyaluronan-induced homophilic interaction of CD44v-expressing myeloma cells (2022)
  • Author(s): Jiro Kikuchi, Nobuyuki Kodama, Masataka Takeshita, Tomoko Hishima, Sho Ikeda, Takahiro Kobayashi, Yoshiaki Kuroda, Michihiro Uchiyama, Naoki Osada, Bjarne Bogen, Hiroshi Yasui, Naoto Takahashi, Akiyoshi Miwa, Yusuke Furukawa
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Osteoclasts robustly express SLAMF7 and secrete soluble SLAMF7 (2022)
  • Author(s): Hirofumi Tenshin, Takeshi Harada, Yusuke Inoue, Jiro Kikuchi, Asuka Oda, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Tomoko Maruhashi, Mamiko Takahashi, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Masahiro Hiasa, Jumpei Teramachi, Yusuke Furukawa, Masahiro Abe
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] Extramedullary diseases originate from hyaluronan-induced homophilic cell-cell interaction of myeloma cells. (2021)
  • Author(s): Kikuchi Jiro, Kodama Nobuyuki, Takeshita Masataka, Hijima Tomoko, Ikeda Sho, Kobayashi Takahiro, Kuroda Yoshiaki, Uchiyama Michihiro, Osada Naoki, Koyama Daisuke, Bogen Bjarne, Yasui Hiroshi, Takahashi Naoto, Miwa Akiyoshi, Furukawa Yusuke
  • Organizer: 第46回日本骨髄腫学会学術集会
• [Presentation] Identification of suitable drugs to be combined with venetoclax for the treatment of multiple myeloma (2021)
  • Author(s): Osada Naoki, Kikuchi Jiro, Koyama Daisuke, Kuroda Yoshiaki, Yasui Hiroshi, Leverson JD, Furukawa Yusuke.
  • Organizer: 第46回日本骨髄腫学会学術集会
• [Presentation] Extramedullary diseases originate from hyaluronan-induced homophilic cell-cell interaction of myeloma cells. (2021)
  • Author(s): Kikuchi Jiro, Kodama Nobuyuki, Takeshita Masataka, Hijima Tomoko, Ikeda Sho, Kobayashi Takahiro, Kuroda Yoshiaki, Uchiyama Michihiro, Osada Naoki, Koyama Daisuke, Bogen Bjarne, Yasui Hiroshi, Takahashi Naoto, Miwa Akiyoshi, Furukawa Yusuke
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] c-FOS mediates IMiDs resistance acting as a co-activator of IKZF1-target genes in multiple myeloma. (2021)
  • Author(s): Osada Naoki, Kikuchi Jiro, Yasui Hiroshi, Furukawa Yusuke.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7 (2020)
  • Author(s): Kikuchi Jiro、Hori Mitsuo、Iha Hidekatsu、Toyama-Sorimachi Noriko、Hagiwara Shotaro、Kuroda Yoshiaki、Koyama Daisuke、Izumi Tohru、Yasui Hiroshi、Suzuki Atsushi、Furukawa Yusuke
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] AMP‐activated protein kinase activation primes cytoplasmic translocation and autophagic degradation of the BCR‐ABL protein in CML cells (2020)
  • Author(s): Koyama Daisuke、Kikuchi Jiro、Kuroda Yoshiaki、Ohta Masatsugu、Furukawa Yusuke
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Bone marrow stromal cell-mediated degradation of CD20 leads to primary rituximab resistance in mantle cell lymphoma (2020)
  • Author(s): Kuroda Yoshiaki、Yashima-Abo Akiko、Koyama Daisuke、Kikuchi Jiro、Mori Shigehisa、Ito Shigeki、Furukawa Yusuke
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Kinetics of cytokine receptor internalization under steady-state conditions affects growth of neighboring blood cells (2020)
  • Author(s): Nagamachi Akiko、Kikuchi Jiro、Kanai Akinori、Furukawa Yusuke、Inaba Toshiya
  • Organizer: 第82回日本血液学会学術集会
• [Remarks] 多発性骨髄腫の抗体薬エロツズマブの新たな作用機序を発見
  • URL: https://www.jichi.ac.jp/news/research/20190820/