TY - JOUR
T1 - IGF-IR determines the fates of BCR/ABL leukemia
AU - Xie, Jingjing
AU - Chen, Xiaoli
AU - Zheng, Junke
AU - Li, Chunling
AU - Stacy, Satomi
AU - Holzenberger, Martin
AU - Hu, Xuemei
AU - Zhang, Chengcheng
N1 - Publisher Copyright:
© 2015 Xie et al.; licensee Biomed Central.
PY - 2015
Y1 - 2015
N2 - Background: The tyrosine kinase receptor insulin-like growth factor 1 receptor (IGF-IR) contributes to the initiation and progression of many types of malignancies. We previously showed that IGF-2, which binds IGF-IR, is an extrinsic factor that supports the ex vivo expansion of hematopoietic stem cells (HSCs). We also demonstrated that IGF-IR is not required for HSC activity in vivo. Methods and results: Here we investigated the role of IGF-IR in chronic myeloid leukemia (CML) using the retroviral BCR/ABL transplantation mouse model. Existing antibodies against IGF-IR are not suitable for flow cytometry; therefore, we generated a fusion of the human IgG Fc fragment with mutant IGF-2 that can bind to IGF-IR. We used this fusion protein to evaluate mouse primary hematopoietic populations. Through transplantation assays with IGF-IR+ and IGF-IR-cells, we demonstrated that IGF-IR is expressed on all mouse HSCs. The expression of IGF-IR is much higher on CML cells than on acute lymphoblastic leukemia (ALL) cells. The depletion of IGF-IR expression in BCR/ABL+ cells led to the development of ALL (mostly T cell ALL) but not CML. Lack of IGF-IR resulted in decreased self-renewal of the BCR/ABL+ CML cells in the serial replating assay. Conclusion: IGF-IR regulates the cell fate determination of BCR/ABL+ leukemia cells and supports the self-renewal of CML cells.
AB - Background: The tyrosine kinase receptor insulin-like growth factor 1 receptor (IGF-IR) contributes to the initiation and progression of many types of malignancies. We previously showed that IGF-2, which binds IGF-IR, is an extrinsic factor that supports the ex vivo expansion of hematopoietic stem cells (HSCs). We also demonstrated that IGF-IR is not required for HSC activity in vivo. Methods and results: Here we investigated the role of IGF-IR in chronic myeloid leukemia (CML) using the retroviral BCR/ABL transplantation mouse model. Existing antibodies against IGF-IR are not suitable for flow cytometry; therefore, we generated a fusion of the human IgG Fc fragment with mutant IGF-2 that can bind to IGF-IR. We used this fusion protein to evaluate mouse primary hematopoietic populations. Through transplantation assays with IGF-IR+ and IGF-IR-cells, we demonstrated that IGF-IR is expressed on all mouse HSCs. The expression of IGF-IR is much higher on CML cells than on acute lymphoblastic leukemia (ALL) cells. The depletion of IGF-IR expression in BCR/ABL+ cells led to the development of ALL (mostly T cell ALL) but not CML. Lack of IGF-IR resulted in decreased self-renewal of the BCR/ABL+ CML cells in the serial replating assay. Conclusion: IGF-IR regulates the cell fate determination of BCR/ABL+ leukemia cells and supports the self-renewal of CML cells.
KW - Acute lymphoblastic leukemia
KW - BCR/ABL
KW - Chronic myeloid leukemia
KW - Hematopoietic stem cells
KW - IGF-IR
KW - Leukemia
KW - Tyrosine kinase receptor
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U2 - 10.1186/s13045-015-0106-8
DO - 10.1186/s13045-015-0106-8
M3 - Article
C2 - 25648584
AN - SCOPUS:84924200543
SN - 1756-8722
VL - 8
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 3
ER -