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Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling.

ABSTRACT: Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for patients with ZAP-70 expression in CLL cells. The tyrosine kinase inhibitor gefitinib has been shown to be effective at induce apoptosis in acute myeloid leukemia through inhibition of Syk. In this study, we sought to test the efficacy of gefitinib in primary human ZAP-70+ CLL cells. We demonstrate that gefitinib preferentially induces cell death in ZAP-70-expressing CLL cells with a median IC50 of 4.5 ?M. In addition, gefitinib decreases the viability of ZAP-70+ Jurkat T leukemia cells but fails to affect T cells from CLL patients. Western blot analysis shows gefitinib reduces both basal and B-cell receptor (BCR)-stimulated phosphorylation of Syk/ZAP-70, ERK, and Akt in ZAP-70+ CLL cells. Moreover, gefitinib inhibits the pro-survival response from BCR stimulation and decreases pro-survival proteins such as Mcl-1. Finally, ZAP-70 expression sensitizes Raji cells to gefitinib treatment. These results demonstrate that gefitinib specifically targets ZAP-70+ CLL cells and inhibits the BCR cell survival pathway leading to apoptosis. This represents the likelihood of tyrosine kinase inhibitors being effective targeted treatments for ZAP-70+ CLL cells.

SUBMITTER: Dielschneider RF

PROVIDER: S-EPMC4649506 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling.

Dielschneider R F RF Xiao W W Yoon J-Y JY Noh E E Banerji V V Li H H Marshall A J AJ Johnston J B JB Gibson S B SB

Cell death & disease 20141002

Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for patients with ZAP-70 expression in CLL cells. The tyrosine kinase inhibitor gefitinib has been shown to be effective at induce apoptosis in acute myeloid leukemia through inhibition of ...[more]

PMID: 25275600

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Project description:Several studies demonstrated IgVH mutation status and ZAP-70 expression as the most relevant prognostic markers in CLL, suggesting the separation of two patient subgroups: with good (MTZAP-70-) and poor prognosis (UMZAP-70+). We determined gene expression of B cells in 112 CLL patients divided into three classes: the first with IgVHMT and ZAP-70-, the second with IgVHUM and ZAP-70+, and the third included both IgVHUM ZAP-70- and IgVHMT ZAP-70+. We found LPL, AGPAT2, MBOAT1, CHPT1, AGPAT4, PLD1 genes encoding enzymes involved in lipid (glycerolipid/glycerophospholipid) metabolism overexpressed in UMZAP-70+. In addition, this study demonstrates the role of ARSD, a gene belonging to the sphingolipid metabolism, as a new gene significantly overexpressed in UMZAP-70+ in respect to MTZAP-70-. ARSD protein was found at significantly higher concentrations in UMZAP-70+ compared to MTZAP-70- CLL B cells and B cells from healthy individuals by Western blotting. Statistical analysis identified a strong correlation between ARSD and IgVH mutation status; ARSD protein level was associated with the requirement of therapy for CLL patients and for this purpose it is as good as IgVH mutational status. Our study highlights ARSD as a promising new prognostic factor in CLL and sphingolipid metabolism as a putative new biological mechanism in CLL. In this study we performed gene expression profiling of B cells on 112 CLL patients divided into three classes based on IgVH mutational status and ZAP-70 protein expression: class one with mutated IgVH and ZAP-70-, class two with unmutated IgVH and ZAP-70+, and class three included CLL patients with unmutated IgVH and ZAP-70-, or mutated IgVH and ZAP-70+, respectively. The decision to divide CLL patients in three categories was due to the clinical feature and the molecular heterogeneity of CLL, in order to elaborate different molecular signature capable of reveal biological mechanisms, and to identify new potential molecular predictors for prognostic assessment or genetic risk. RNA was extracted and quantified for high-density oligonucleotide microarrays Human Genome U133 Plus 2.0 GeneChip (Affymetrix, Santa Clara, CA). A first cohort of 62 subjects was analyzed using GeneChip Expression 3' Amplification One-Cycle Target Labeling Kit, while a second cohort of 50 subjects using GeneChip 3'IVT Express Kit, according to manufacturerM-bM-^@M-^Ys protocol (Affymetrix), respectively.

Dataset Information

Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling.

Publications

Gefitinib targets ZAP-70-expressing chronic lymphocytic leukemia cells and inhibits B-cell receptor signaling.

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