Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells by Toshihiko Tanno, Yiting Lim, Qiuju.

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Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells by Toshihiko Tanno, Yiting Lim, Qiuju Wang, Marta Chesi, P. Leif Bergsagel, Geoff Matthews, Ricky W. Johnstone, Nilanjan Ghosh, Ivan Borrello, Carol Ann Huff, and William Matsui Blood Volume 123(5):725-733 January 30, 2014 ©2014 by American Society of Hematology

GDF15 enhances the clonogenic growth of MM GDF15 enhances the clonogenic growth of MM. (A) Primary and secondary colony formation (CFC) of NCI-H929 cells cultured with GDF15 for 7 days. *P < .05 compared with 0 ng/mL GDF15. GDF15 enhances the clonogenic growth of MM. (A) Primary and secondary colony formation (CFC) of NCI-H929 cells cultured with GDF15 for 7 days. *P < .05 compared with 0 ng/mL GDF15. (B) Survival of NSG mice after injection of NCI-H929 cells treated ex vivo with or without GDF15 (100 ng/mL) for 14 days (n = 5 for each condition). (C) Survival of mice after secondary transplantation of GDF15 cells. (D) MM colony formation by primary clinical bone marrow specimens after treatment with GDF15 ± anti-GDF15 antibody (Ab) for 3 days. *P < .05 compared with 0 ng/mL GDF15. Toshihiko Tanno et al. Blood 2014;123:725-733 ©2014 by American Society of Hematology

GDF15 activity is dependent on AKT and SOX2. GDF15 activity is dependent on AKT and SOX2. (A) Western blot detection of phosphorylated AKT, BMI-1, and SOX2 expression by NCI-H929 cells after treatment with GDF (100 ng/mL). (B) Serial colony formation after treatment with GDF15 and the Akti 124018 for 3 days. *P < .05 compared with 0 ng/mL GDF15. (C) Western blot analysis of SOX2 after treatment with GDF15 and AKT inhibitor. (D) Serial colony formation of NCI-H929 cells after transfection of SOX2 or control short interfering RNA (siRNA) and treatment with GDF15 for 3 days. *P < .05 compared with scramble control and 0 ng/mL GDF15. The inset shows SOX2 expression by qRT-PCR 3 days after transfection. Toshihiko Tanno et al. Blood 2014;123:725-733 ©2014 by American Society of Hematology

BMSC-derived GDF15 enhances clonogenic MM growth. BMSC-derived GDF15 enhances clonogenic MM growth. (A) Serial colony formation by NCI-H929 cells cocultured with MM BMSC in the presence or absence of anti-GDF15 antibody (Ab) for 4 days. *P < .05 compared with NCI-H929 cell only. (B) GDF15 secretion by primary BMSCs derived from HVs (light gray) and MM patients (dark gray) cultured alone or with NCI-H929 (H929), Granta519, Jeko-1, or normal CD138+ plasma cells. Cell culture inserts inhibited cell-cell contacts between NCI-H929 cells and MM BMSCs. *P < .05 compared with MM BMSC only. (C) Survival of Gdf15null or wild-type (WT) mice after injection of Vk*Myc MM cells (n = 5 for each group). (D) Secondary transplantation of BM derived from mice initially engrafted with Vk*Myc MM cells. Toshihiko Tanno et al. Blood 2014;123:725-733 ©2014 by American Society of Hematology

GDF15 expands MM TICs. (A) Relative cell numbers after treatment of unfractionated, CD138neg, and CD138+ NCI-H929 cells with GDF15 for 7 days. GDF15 expands MM TICs. (A) Relative cell numbers after treatment of unfractionated, CD138neg, and CD138+ NCI-H929 cells with GDF15 for 7 days. (B) Absolute number of CD138neg NCI-H929 cells quantified by flow cytometry after treatment with GDF15. (C) Relative expansion of prospectively isolated CD138neg NCI-H929 cells by GDF15. (D) Relative clonogenic recovery of CD138neg NCI-H929 cells after treatment with GDF15 for 7 days. (E) Relative clonogenic recovery of CD138+ NCI-H929 cells after treatment with GDF15 for 7 days. (F) Absolute number of ALDH+ NCI-H929 cells quantified by flow cytometry after treatment with GDF15. *P < .05 compared with 0 ng/mL GDF15. Toshihiko Tanno et al. Blood 2014;123:725-733 ©2014 by American Society of Hematology

Serum GDF15 levels and clinical outcomes in MM Serum GDF15 levels and clinical outcomes in MM. Progression-free survival of MM patients based on increasing or decreasing serum levels of GDF15. Serum GDF15 levels and clinical outcomes in MM. Progression-free survival of MM patients based on increasing or decreasing serum levels of GDF15. Toshihiko Tanno et al. Blood 2014;123:725-733 ©2014 by American Society of Hematology

Interactions between MM plasma cells, TICs, and BMSCs Interactions between MM plasma cells, TICs, and BMSCs. The interaction between BMSCs and mature MM plasma cells induces GDF15 secretion and enhances the self-renewal of MM CSCs by AKT, SOX2, and BMI-1. Interactions between MM plasma cells, TICs, and BMSCs. The interaction between BMSCs and mature MM plasma cells induces GDF15 secretion and enhances the self-renewal of MM CSCs by AKT, SOX2, and BMI-1. Subsequent production of mature tumor cells further promotes this process. Toshihiko Tanno et al. Blood 2014;123:725-733 ©2014 by American Society of Hematology