Leukemic lymphoblasts, a novel expression site of coagulation factor XIII subunit A

Kiss, Flóra; Hevessy, Zsuzsanna; Veszprémi, Anikó; Katona, Éva; Kiss, Csongor; Vereb, György; Muszbek, László; Kappelmayer, János

doi:10.1160/th06-05-0270

Cited by 19 publications

(7 citation statements)

References 25 publications

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“…To rule out technical artifacts, blasts were also investigated in an indirect labeling system with the same polyclonal antihuman FXIII-A as used for immunoblotting. The staining characteristics were similar to that previously observed for leukemic lymphoblasts [18].…”

Section: Detection Of Fxiii-a In Apl Cells By Clsmsupporting

confidence: 87%

“…In later studies, this cytoplasmic enzyme proved useful in the identification of leukemic samples and it differentiated myeloblasts from monoblasts and promonocytes [12]. More recently, we have also identified leukemic lymphoblasts as a source of FXIII-A [18]. Whether this marker is a prognostic factor in childhood B-ALL is presently under investigation.…”

Section: Discussionmentioning

confidence: 89%

“…It was also important to establish the amount of FXIII-A since in our previous studies the FXIII-A content of various cell types was largely different [9,18]. We obtained sufficient cell number from two clinical cases that showed a high FXIII-A content, on average the amount of FXIII-A was in the range of blood platelets and 10-fold higher than that described previously for leukemic lymphoblasts [18]. Although, it should be noted that APL blasts are much larger than platelets thus the intracellular concentration of FXIII-A is considerably lower.…”

Section: Discussionmentioning

confidence: 99%

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Expression of coagulation factor XIII subunit A in acute promyelocytic leukemia

Simon¹,

Bagoly²,

Hevessy³

et al. 2012

Cytometry Part B Clinical

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Leukemic cells often express markers, which are not characteristic of their particular cell lineage. In this study, we identified the ''A'' subunit of coagulation factor XIII (FXIII-A) in leukemic promyelocytes in de novo AML M3 cases. The cytoplasmic presence of factor XIII-A has previously been shown only in platelets/megakaryocytes and monocytes/macrophages. Furthermore, more recently we described the presence of FXIII-A in leukemic lymphoblasts. We studied 14 patients with this rare type of acute leukemia in a period of 4 years and investigated their bone marrow samples by 3-color flow cytometry upon diagnosis, mainly focusing on FXIII-A expression of leukemic cells. We detected FXIII-A also by ELISA, Western-blot, and confocal laser scanning microscopy. This was a homogenous group of AML M3 patients with translocation t(15;17)(q22;q21) detected by fluorescence in situ hybridization (FISH). In 10 out of 14 samples, FXIII-A was detectable by flow cytometry and was coexpressed with markers characteristic for leukemic promyleocytes (CD45dim/CD131/CD331/ CD1171/cyMPO1 and HLA-DR-/CD342/CD142/CD152). Staining for the markers GPIIb and GPIX were negative, and FXIII-A was identified in the cytoplasm of the cells by confocal microscopy in a relatively high quantity, as measured by ELISA. By Western blot analysis we could identify FXIII-A in the native 82 kDa form and in cleaved forms corresponding to cleavage products observed when purified FXIII-A was treated by human neutrophil elastase. This novel expression site of FXIII-A in AML M3 can be considered as a leukemia associated immunophenotype and may have pathophysiological significance. V C 2012 International Clinical Cytometry Society

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Section: Detection Of Fxiii-a In Apl Cells By Clsmsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Expression of coagulation factor XIII subunit A in acute promyelocytic leukemia

Simon¹,

Bagoly²,

Hevessy³

et al. 2012

Cytometry Part B Clinical

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“…FXIII-A is a useful marker of acute myeloid leukemia (AML) of the monocyte and megakaryocyte lineages (31–34). However, its expression in BCP-ALL blasts was an unexpected finding, since, in contrast to the normal myeloid counterparts of AML blasts, normal B-lymphocytes and their precursors do not express FXIII-A (8). Intracellular expression of FXIII-A protein can be consistently demonstrated in about two thirds of pediatric BCP-ALL samples by FC.…”

Section: Discussionmentioning

confidence: 99%

“…Our group identified BCP-ALL blasts as a new expression site for coagulation factor XIII subunit A (FXIII-A). In contrast to the BCP-ALL blasts, neither normal bone marrow B-cell progenitors, nor mature B-cells, both normal and leukemic once, nor T-lymphoblasts/lymphocytes express FXIII-A (8). We observed three characteristic expression patterns by flow cytometry (FC): FXIII-A negative, FXIII-A dim, and FXIII-A bright lymphoblasts with about two thirds of pediatric BCP-ALL patients representing FXIII-A positive (FXIII-A dim and bright) cases.…”

Section: Introductionmentioning

confidence: 91%

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

et al. 2019

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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.

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A coagulation factor becomes useful in the study of acute leukemias: Studies with blood coagulation factor XIII

et al. 2007

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The intracellular form of the coagulation factor XIII has previously been identified by immunomorphological techniques using polyclonal antibodies. In these studies, only the A subunit (FXIII-A) was detectable in megakaryocytes/platelets and in monocytes/ macrophages. We developed several novel monoclonal antibody clones directed to both subunits (FXIII-A and FXIII-B) and investigated their appearance in normal and leukemic cells. By using 3-and 4-color flow cytometry FXIII expression was investigated in normal peripheral blood and bone marrow samples and in acute myeloblastic (AML) and lymphoblastic (ALL) leukemia cases. Samples were studied by Western blotting and confocal laser scanning microscopy. With a previously published ELISA assay applying two monoclonal antibodies directed to different epitopes in FXIII-A, we were able to measure the intracytoplasmic content of FXIII-A in normal cells and leukemic blasts. FXIII-A was detectable in normal peripheral blood monocytes and in large quantities in platelets, but both cell types were negative for FXIII-B. There was no surface staining for FXIII-A, it only appeared intracellularly. In samples derived from patients with AML M4 and M5, FXIII-A sensitively identified blast cells. Although normal lymphocytes do not express FXIII-A, 40% of ALL cases showed significant FXIII-A expression as determined by flow cytometry. FXIII-A positivity of lymphoblasts was verified by Western blotting, ELISA, and confocal laser scanning microscopy cytometry. These data provide evidence that FXIII-A is a sufficiently sensitive marker in differentiating myeloblasts and monoblasts and is suitable for identifying leukemia-associated phenotypes in ALL. ' International Society for Analytical CytologyKey terms factor XIII; flow cytometry; acute leukemia phenotype HEMATOLOGICAL malignancies are exceptional in the sense that unlike solid tumors, right from the beginning they are spread all over the body since cancer cells appear in the blood. Acute leukemias represent 85% of all leukemias in children and 45% in adults. In childhood, $80% of acute leukemias are lymphoblastic and 15-20% are myeloblastic (1), whereas this proportion is basically reversed in adults. Leukemic cells display phenotypes that are either present in normal precursors or is unique for the leukemic population also referred to as leukemia-associated immunophenotype (LAIP) or aberrant phenotype. Several publications described LAIP on blasts in acute leukemias (2-5). The major features are lineage infidelity and lineage promiscuity, where leukemic cells express antigens associated with a different cell line, e.g., CD13 and CD33 myeloid-associated antigens in precursor-B acute lymphoblastic leukemia (ALL) (6) or CD7 T-cell marker expression in neoplastic myeloblasts (7). In case of asynchronous differentiation, markers of different maturational stages are expressed simultaneously, like the coexpression of CD10 and CD20 in B-ALL (8) or CD117/CD15 coexpression in acute myeloid leukemia (AML) (9). Antigen

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Leukemic lymphoblasts, a novel expression site of coagulation factor XIII subunit A

Cited by 19 publications

References 25 publications

Expression of coagulation factor XIII subunit A in acute promyelocytic leukemia

Expression of coagulation factor XIII subunit A in acute promyelocytic leukemia

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

A coagulation factor becomes useful in the study of acute leukemias: Studies with blood coagulation factor XIII

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