Abstract
BackgroundThe role of IGF binding protein 2 (IGFBP2) in cancer development is intriguing. Previously we identified IGFBP2 as an extrinsic factor that supports the activity of hematopoietic stem cells (HSCs).Methods and resultsHere we investigated the role of IGFBP2 in in human leukemia cells and in the retroviral AML1-ETO9a transplantation acute myeloid leukemia (AML) mouse model.ResultsIGFBP2 is highly expressed in certain human AML and acute lymphoblastic leukemia (ALL) cells. Inhibition of expression of endogenous IGFBP2 in human leukemia cells led to elevated apoptosis and decreased migration and, consistently, to decreased activation of AKT and other signaling molecules. We also studied the effects of IGFBP2 knockout in the retroviral AML1-ETO9a transplantation AML mouse model. The deletion of IGFBP2 in donor AML cells significantly decreased leukemia development in transplanted mice. Lack of IGFBP2 resulted in upregulation of PTEN expression and downregulation of AKT activation, in the mouse AML cells. The treatment of IGFBP2 deficient AML cells with a PTEN inhibitor restored the wild-type colony forming ability. The deletion of IGFBP2 also led to decreased AML infiltration into peripheral organs and tissues, suggesting that IGFBP2 is required for the migration of AML cells out of bone marrow.ConclusionIGFBP2 is a critical cell-autonomous factor that promotes the survival and migration of acute leukemia cells.
Highlights
Acute myeloid leukemia (AML) is characterized by rapid proliferation of immature myeloid blasts in the bone marrow
IGF binding protein 2 (IGFBP2) is highly expressed in certain human AML cells We performed an in silico analysis of IGFBP2 mRNA expression in different subtypes of human AML based on data from the TCGA AML database
IGFBP2 mRNA was expressed at the highest levels in the M3 subtype NB4 AML cells, it was highly expressed in some other AML and B cell-derived acute lymphoblastic leukemia (ALL) (B-ALL) cells including MV4-11 (M5 AML), U937 (B-ALL), and RCH-ACV (B-ALL) (Figure 1B)
Summary
Acute myeloid leukemia (AML) is characterized by rapid proliferation of immature myeloid blasts in the bone marrow. It is the most common acute leukemia affecting adults and accounts for about 1.2% of cancer deaths in the United States each year. To effectively treat AML, new molecular targets and therapeutic approaches need to be identified. IGFBPs modulate the biological effects of IGFs by controlling IGF distribution, function, and. The role of IGF binding protein 2 (IGFBP2) in cancer development is intriguing. We identified IGFBP2 as an extrinsic factor that supports the activity of hematopoietic stem cells (HSCs)
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