Novel signaling axis in CML-initiating cells

Zhang, Cheng Cheng

doi:10.1182/blood-2014-03-560359

Cited by 2 publications

(1 citation statement)

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“…Is IGF-IR signaling in CML cells independent of BCR/ABL-induced signaling? How does IGF signaling, together with other extrinsic and intrinsic pathways (IL-6, Wnt, Hedgehog, BMPs, selectin, TGF-β, Alox5, CD25, among others) [ 9 , 28 - 33 ], regulate the fates of CML cells including self-renewal, differentiation, apoptosis, and migration? Given extensive aberrant signaling in CML cells, we expect that the combined use of TKIs and inhibition of a limited number of key extrinsic pathways, including IGF-IR signaling, will lead to the development of novel strategies for treating CML.…”

Section: Discussionmentioning

confidence: 99%

IGF-IR determines the fates of BCR/ABL leukemia

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 99%