IGF-IR determines the fates of BCR/ABL leukemia

Jingjing Xie, Xiaoli Chen, Junke Zheng, Chunling Li, Satomi Stacy, Martin Holzenberger, Xuemei Hu, Chengcheng Zhang

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number3
JournalJournal of Hematology and Oncology
Volume8
Issue number1
DOIs
StatePublished - 2015

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia
Myeloid Cells
Hematopoietic Stem Cells
Insulin-Like Growth Factor II
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Transplantation
Immunoglobulin Fc Fragments
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Growth Factor Receptors
Insulin-Like Growth Factor I
Flow Cytometry
Immunoglobulin G
Antibodies
Population
Neoplasms
Proteins

Keywords

  • Acute lymphoblastic leukemia
  • BCR/ABL
  • Chronic myeloid leukemia
  • Hematopoietic stem cells
  • IGF-IR
  • Leukemia
  • Tyrosine kinase receptor

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research
  • Molecular Biology

Cite this

IGF-IR determines the fates of BCR/ABL leukemia. / Xie, Jingjing; Chen, Xiaoli; Zheng, Junke; Li, Chunling; Stacy, Satomi; Holzenberger, Martin; Hu, Xuemei; Zhang, Chengcheng.

In: Journal of Hematology and Oncology, Vol. 8, No. 1, 3, 2015.

Research output: Contribution to journalArticle

Xie, J, Chen, X, Zheng, J, Li, C, Stacy, S, Holzenberger, M, Hu, X & Zhang, C 2015, 'IGF-IR determines the fates of BCR/ABL leukemia', Journal of Hematology and Oncology, vol. 8, no. 1, 3. https://doi.org/10.1186/s13045-015-0106-8
Xie, Jingjing ; Chen, Xiaoli ; Zheng, Junke ; Li, Chunling ; Stacy, Satomi ; Holzenberger, Martin ; Hu, Xuemei ; Zhang, Chengcheng. / IGF-IR determines the fates of BCR/ABL leukemia. In: Journal of Hematology and Oncology. 2015 ; Vol. 8, No. 1.
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AU - Xie, Jingjing

AU - Chen, Xiaoli

AU - Zheng, Junke

AU - Li, Chunling

AU - Stacy, Satomi

AU - Holzenberger, Martin

AU - Hu, Xuemei

AU - Zhang, Chengcheng

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

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KW - Leukemia

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