Abstract
BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with the need for treatment optimization. Previously, high expression of Insulin-like growth factor binding protein 7 (IGFBP7), a member of the IGF system, was identified as negative prognostic factor in adult T-ALL patients. Since aberrant IGFBP7 expression was observed in a variety of neoplasia and was relevant for prognosis in T-ALL, we investigated the functional role of IGFBP7 in Jurkat and Molt-4 cells as in vitro models for T-ALL.MethodsJurkat and Molt-4 cells were stably transfected with an IGFBP7 over-expression vector or the empty vector as control. Proliferation of the cells was assessed by WST-1 assays and cell cycle status was measured by flow-cytometry after BrDU/7-AAD staining. The effect of IGFBP7 over-expression on sensitivity to cytostatic drugs was determined in AnnexinV/7-AAD assays. IGF1-R protein expression was measured by Western Blot and flow-cytometric analysis. IGF1-R associated gene expression profiles were generated from microarray gene expression data of 86 T-ALL patients from the Microarrays Innovations in Leukemia (MILE) multicenter study.ResultsIGFBP7-transfected Jurkat cells proliferated less, leading to a longer survival in a nutrient–limited environment. Both IGFBP7-transfected Jurkat and Molt-4 cells showed an arrest in the G0/G1 cell cycle phase. Furthermore, Jurkat IGFBP7-transfected cells were resistant to vincristine and asparaginase treatment. Surface expression and whole protein measurement of IGF1-R protein expression showed a reduced abundance of the receptor after IGFBP7 transfection in Jurkat cells. Interestingly, combination of the IGF1-R inhibitor NPV-AEW541 restored sensitivity to vincristine in IGFBP7-transfected cells. Additionally, IGF1-R associated GEP revealed an up-regulation of important drivers of T-ALL pathogenesis and regulators of chemo-resistance and apoptosis such as NOTCH1, BCL-2, PRKCI, and TP53.ConclusionThis study revealed a proliferation inhibiting effect of IGFBP7 by G0/G1 arrest and a drug resistance-inducing effect of IGFBP7 against vincristine and asparaginase in T-ALL. These results provide a model for the previously observed association between high IGFBP7 expression and chemotherapy failure in T-ALL patients. Since the resistance against vincristine was abolished by IGF1-R inhibition, IGFBP7 could serve as biomarker for patients who may benefit from therapies including IGF1-R inhibitors in combination with chemotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1677-z) contains supplementary material, which is available to authorized users.
Highlights
T-cell acute lymphoblastic leukemia (T-Acute lymphoblastic leukemia (ALL)) is a genetically heterogeneous disease with the need for treatment optimization
Insulin-like growth factor binding protein 7 (IGFBP7) over-expression sustains proliferation of Jurkat cells In order to determine the effect of IGFBP7 over-expression in TALL, IGFBP7 was successfully over-expressed in Jurkat and in Molt-4 cells
Since vincristine and asparaginase are both routinely used in current chemotherapy regimens the results provide an explanation for the observed link between aberrantly high IGFBP7 expression and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL) patients
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with the need for treatment optimization. High expression of Insulin-like growth factor binding protein 7 (IGFBP7), a member of the IGF system, was identified as negative prognostic factor in adult T-ALL patients. Acute lymphoblastic leukemia (ALL) is a heterogeneous disease which survival rate has greatly improved during the last decades due to improvement in risk stratification and adapted treatment strategies. Despite these advances, adult T-cell acute lymphoblastic leukemia (T-ALL) patients only have a survival of 40–70 %, depending on protocol and age group. For example IGFBP3 was revealed to bind to a receptor and nuclear localization was observed for IGFBP2, −3 and −5 [6,7,8]
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