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

ABSTRACT: Background: 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. Methods: 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 in situ 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. Results: We demonstrated, for the first time, the general expression of F13A1 gene in pediatric BCP-ALL samples. The intensity of F13A1 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 ANGPTL2, EHMT1 FOXO1, HAP1, NUCKS1, NUP43, PIK3CG, RAPGEF5, SEMA6A, SPIN1, TRH, and WASF2 followed the pattern of change in the intensity of the expression of the F13A1 gene. Common enhancer elements of these genes revealed by in silico analysis suggest that common transcription factors may regulate the expression of these genes in a similar fashion. PLAC8 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. DFFA, GIGYF1, GIGYF2, and INTS3 were upregulated and CD3G 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. Conclusions: 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.

SUBMITTER: Gyurina K

PROVIDER: S-EPMC6823876 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Gyurina Katalin K Kárai Bettina B Ujfalusi Anikó A Hevessy Zsuzsanna Z Barna Gábor G Jáksó Pál P Pálfi-Mészáros Gyöngyi G Póliska Szilárd S Scholtz Beáta B Kappelmayer János J Zahuczky Gábor G Kiss Csongor C

Frontiers in oncology 20191025

<b>Background:</b> 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. <b>Methods:</b> RNA was extracted from bone marrow lymphoblasts of 42 pediatr ...[more]

PMID: 31709175

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Project description:Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, and the second leading cause of pediatric cancer-related death in developed countries. While the cure rate for newly diagnosed ALL is excellent, the genetic heterogeneity and chemoresistance of leukemia cells at relapse makes individualized curative treatment plans difficult. We hypothesize that genetic events would coalesce into a finite number of protein signatures that could guide the design of individualized therapy. Custom reverse-phase protein arrays were produced from pediatric ALL (n = 73) and normal CD34+ (n = 10) samples with 194 validated antibodies. Proteins were allocated into 31 protein functional groups (PFG) to analyze them in the context of other proteins, based on known associations from the literature. The optimal number of protein clusters was determined for each PFG. Protein networks showed distinct transition states, revealing "normal-like" and "leukemia-specific" protein patterns. Block clustering identified strong correlation between various protein clusters that formed 10 protein constellations. Patients that expressed similar recurrent combinations of constellations comprised 7 distinct signatures, correlating with risk stratification, cytogenetics, and laboratory features. Most constellations and signatures were specific for T-cell ALL or pre-B-cell ALL; however, some constellations showed significant overlap. Several signatures were associated with Hispanic ethnicity, suggesting that ethnic pathophysiologic differences likely exist. In addition, some constellations were enriched for "normal-like" protein clusters, whereas others had exclusively "leukemia-specific" patterns.Implications: Recognition of proteins that have universally altered expression, together with proteins that are specific for a given signature, suggests targets for directed combinatorial inhibition or replacement to enable personalized therapy. Mol Cancer Res; 16(8); 1263-74. ©2018 AACRSee related article by Hoff et al., p. 1275.

Project description:Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL.

Dataset Information

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

Publications

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

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