AUTHOR=Gyurina Katalin , Kárai Bettina , Ujfalusi Anikó , Hevessy Zsuzsanna , Barna Gábor , Jáksó Pál , Pálfi-Mészáros Gyöngyi , Póliska Szilárd , Scholtz Beáta , Kappelmayer János , Zahuczky Gábor , Kiss Csongor 

TITLE=Coagulation FXIII-A Protein Expression Defines Three Novel Sub-populations in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia Characterized by Distinct Gene Expression Signatures

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01063

DOI=10.3389/fonc.2019.01063

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Leukemic B-cell precursor (BCP) lymphoblasts were identified as a novel expression site for coagulation factor XIII subunit A (FXIII-A). Flow cytometry (FC) revealed three distinct expression patterns, i.e., FXIII-A negative, FXIII-A dim, and FXIII-A bright subgroups. The FXIII-A negative subgroup was significantly associated with the “B-other” genetic category and had an unfavorable disease outcome.</p><p><bold>Methods:</bold> RNA was extracted from bone marrow lymphoblasts of 42 pediatric patients with BCP-acute lymphoblastic leukemia (ALL). FXIII-A expression was determined by multiparameter FC. Genetic diagnosis was based on conventional cytogenetic method and fluorescence <italic>in situ</italic> hybridization. Affymetrix GeneChip Human Primeview array was used to analyze global expression pattern of 28,869 well-annotated genes. Microarray data were analyzed by Genespring GX14.9.1 software. Gene Ontology analysis was performed using Cytoscape 3.4.0 software with ClueGO application. Selected differentially expressed genes were validated by RT-Q-PCR.</p><p><bold>Results:</bold> We demonstrated, for the first time, the general expression of <italic>F13A1</italic> gene in pediatric BCP-ALL samples. The intensity of <italic>F13A1</italic> expression corresponded to the FXIII-A protein expression subgroups which defined three characteristic and distinct gene expression signatures detected by Affymetrix oligonucleotide microarrays. Relative gene expression intensity of <italic>ANGPTL2, EHMT1 FOXO1, HAP1, NUCKS1, NUP43, PIK3CG, RAPGEF5, SEMA6A, SPIN1, TRH</italic>, and <italic>WASF2</italic> followed the pattern of change in the intensity of the expression of the <italic>F13A1</italic> gene. Common enhancer elements of these genes revealed by <italic>in silico</italic> analysis suggest that common transcription factors may regulate the expression of these genes in a similar fashion. <italic>PLAC8</italic> was downregulated in the FXIII-A bright subgroup. Gene expression signature of the FXIII-A negative subgroup showed an overlap with the signature of “B-other” samples. <italic>DFFA, GIGYF1, GIGYF2</italic>, and <italic>INTS3</italic> were upregulated and <italic>CD3G</italic> was downregulated in the “B-other” subgroup. Validated genes proved biologically and clinically relevant. We described differential expression of genes not shown previously to be associated with pediatric BCP-ALL.</p><p><bold>Conclusions:</bold> Gene expression signature according to FXIII-A protein expression status defined three novel subgroups of pediatric BCP-ALL. Multiparameter FC appears to be an easy-to-use and affordable method to help in selecting FXIII-A negative patients who require a more elaborate and expensive molecular genetic investigation to design precision treatment.</p>