Journal Article

High STAP1 expression in DUX4-rearranged cases is not suitable as therapeutic target in pediatric B-cell precursor acute lymphoblastic leukemia

Bakker, Marjolein, de Haas, Valerie, Pieters, Rob, Escherich, Gabriele, Hoogkamer, Alex Q., den Boer, Monique L., Boer, Judith M., Steeghs, Elisabeth M. P., Hartman, Quirine J., Stalpers, Femke, de Groot-Kruseman, Hester A.

2018

Overview

Approximately 25% of the pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases are genetically unclassified. More thorough elucidation of the pathobiology of these genetically unclassified (‘B-other’) cases may identify novel treatment options. We analyzed gene expression profiles of 572 pediatric BCP-ALL cases, representing all major ALL subtypes. High expression of STAP1 , an adaptor protein downstream of the B-cell receptor (BCR), was identified in BCR-ABL1 -like and non- BCR-ABL1 -like B-other cases. Limma analysis revealed an association between high expression of STAP1 and BCR signaling genes. However, STAP1 expression and pre-BCR signaling were not causally related: cytoplasmic Igμ levels were not abnormal in cases with high levels of STAP1 and stimulation of pre-BCR signaling did not induce STAP1 expression. To elucidate the role of STAP1 in BCP-ALL survival, expression was silenced in two human BCP-ALL cell lines. Knockdown of STAP1 did not reduce the proliferation rate or viability of these cells, suggesting that STAP1 is not a likely candidate for precision medicines. Moreover, high expression of STAP1 was not predictive for an unfavorable prognosis of BCR-ABL1 -like and non- BCR-ABL1 -like B-other cases. Remarkably, DUX4 -rearrangements and intragenic ERG deletions, were enriched in cases harboring high expression of STAP1 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 38/61 / 631/67/1990/283/2125 / 631/67/2332 / 82/80 / Acute lymphoblastic leukemia / Adaptor Proteins, Signal Transducing - antagonists & inhibitors / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / B-cell receptor / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cell Survival - drug effects / Chromosome Aberrations / Fusion Proteins, bcr-abl - genetics / Gene expression / Homeodomain Proteins - genetics / Humanities and Social Sciences / Humans / Leukemia / Lymphatic leukemia / Lymphocytes B / Medical prognosis / multidisciplinary / Pediatrics / Polymorphism, Single Nucleotide / Precision medicine / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology / Receptors, Antigen, B-Cell - metabolism / RNA Interference / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Therapeutic applications / Transcriptional Regulator ERG - genetics / Transcriptional Regulator ERG - metabolism