Abstract
BackgroundThe 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 resultsHere 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.ConclusionIGF-IR regulates the cell fate determination of BCR/ABL+ leukemia cells and supports the self-renewal of CML cells.
Highlights
Chronic myeloid leukemia (CML) is a hematopoietic malignancy that results from the t(9;22)(q34;q11) Philadelphia (Ph) chromosome translocation, which produces the BCR/ ABL fusion oncogene [1,2,3]
Insulin-like growth factor (IGF)-IR is expressed on the surface of hematopoietic stem cells (HSCs) We previously showed that IGF-2 stimulates ex vivo expansion of HSCs [21]
Because existing antibodies against IGF-2: IGF type receptor (IGF-IR) are not suitable for flow cytometry, we were unable to determine whether IGF-IR was expressed on HSCs
Summary
Chronic myeloid leukemia (CML) is a hematopoietic malignancy that results from the t(9;22)(q34;q11) Philadelphia (Ph) chromosome translocation, which produces the BCR/ ABL fusion oncogene [1,2,3]. Tyrosine kinase inhibitors (TKIs) effectively treat symptoms of CML patients, but the disease is not curable in most cases. Both BCR/ABL dependent and independent mechanisms contribute to TKI resistance. BCR/ABL independent resistance mechanisms result from drug efflux or influx or activation of alternative signaling pathways [8,9]. Novel targets in CML-ICs. The tyrosine kinase receptor insulin-like growth factor 1 receptor (IGF-IR) contributes to the initiation and progression of many types of malignancies. We demonstrated that IGF-IR is not required for HSC activity in vivo
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