IGF-IR determines the fates of BCR/ABL leukemia

Journal of Hematology & Oncology

Cheng Cheng Zhang¹  Xuemei Hu³  Martin Holzenberger²  Satomi Stacy¹  Chunling Li³  Junke Zheng¹  Xiaoli Chen¹  Jingjing Xie³ 

[1] Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA;INSERM and Sorbonne Universities, UPMC, Research Center UMR938, Paris, 75012, France;Taishan Scholar Immunology Program, Binzhou Medical University, Yantai, 264003, Shandong, China

关键词: IGF-IR;    BCR/ABL;    Tyrosine kinase receptor;    Hematopoietic stem cells;    Acute lymphoblastic leukemia;    Chronic myeloid leukemia;    Leukemia;   

Others  :  1133472
DOI  :  10.1186/s13045-015-0106-8

 received in 2014-11-06, accepted in 2015-01-05,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Xie et al.; licensee Biomed Central.

【 图 表 】

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