High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse

Abstract

The online version of this article has a Supplementary Appendix. BackgroundResistance to therapy and subsequent relapse remain major challenges in the clinical management of relapsed childhood acute lymphoblastic leukemia. As the bone marrow environment plays an important role in survival and chemotherapy resistance of leukemia cells by activating different signaling pathways, such as the VLA-4 and PI3K/Akt pathways, we studied the prognostic and biological impact of VLA-4 expression in leukemia cells from children with relapsed B-cell precursor acute lymphoblastic leukemia and its influence on the sensitivity of the leukemia cells to drugs. Design and MethodsVLA-4 expression was quantified by real-time polymerase chain reaction in leukemia cells from 56 patients with relapsed acute lymphoblastic leukemia enrolled in the ALL-REZ BFM 2002 trial of the Berlin-Frankfurt-Münster study group. Gene expression changes related to VLA-4 expression were investigated by microarray-based mRNA profiling. The effect of VLA-4 signaling on proliferation and drug resistance was studied in co-cultures of leukemia and stromal cells. ResultsHigh expression of VLA-4 at first relapse was associated with adverse prognostic factors, poor molecular response to therapy and significantly worse probabilities of event-free and overall survival. VLA-4 expression was an independent prognostic parameter. Comparing gene expression profiles of leukemia cells with high versus low VLA-4 expression, we identified 27 differentially expressed genes primarily involved in the PI3K/Akt, ephrin and Rho GTPase pathways. Blocking of VLA-4 signaling in combination with cytarabine treatment abolished the growth supportive effect of stromal cells. ConclusionsOur results show that high VLA-4 expression is a marker of poor prognosis and a potential therapeutic target in children with relapsed acute lymphoblastic leukemia and confirm that cellular interactions and biological effects related to VLA-4 play a decisive role in the survival of leukemia cells and response to therapy. (ClinicalTrials.gov identifier: NCT00114348)

The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

“…Very late antigen-4 (VLA-4), an α4-, β1-integrin dimer, is a receptor for fibronectin and has been associated with B-cell survival and activation of the phosphatidylinositol-3-kinase signalling pathway in acute leukaemia (17,37). Recently, VLA-4 expression has been identified as a poor prognostic marker and potential therapeutic target in relapsed childhood B-ALL (38). We observed significantly reduced α4-, β1-and β2-integrin mediated adhesion in PBOX-15-treated B-ALL cells concurrently with down-regulation of the respective integrin subunits.…”

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

“…Moreover, ITGA-4 (VLA-4)-mediated signaling during the interaction with stroma cells has been shown to support the survival of leukemia cells mostly through the activation of the PI3K pathway (28,29). VLA-4 expression was validated by QRT-PCR at 2 time points, showing that the VLA-4 mRNA expression decreased significantly after concomitant treatments ( Fig.…”

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

“…LFA-1/ICAM-1 adhesive interactions as well as VCAM-1 and E-selectine molecules are also necessary for the survival of T-ALL cell lines and patient-derived T-ALL cells on BM stroma in vitro [46]. Lastly, B-ALL of relapsed patients have been shown to express high levels of VLA-4, which interacts with VCAM-1 on the stromal cells leading to the differential expression of a battery of genes involved in PI3K/mTOR, Wnt and NFkB signaling pathways [47,48].…”