lewis-x-antigen and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

To study clinical and histopathological features, and diagnosis of mediastinal tumours of haematopoietic and lymphoid tissues (MTHL).. Forty cases of MTHL were analyzed for clinicopathology by microscopy and immunohistochemical staining and in situ hybridization, according to the updated 2008 WHO classification of tumours of haematopoietic and lymphoid tissues.. In 40 cases of MTHL, there were 20 males and 20 females. The ratio of male/female was 1:1. The mean age was 31.8 years and median age was 29 years (range, 12 - 70 years).Superior vena cava syndrome was observed in 28 cases. The specimens of 4 cases were obtained by lumpectomy, whereas 36 cases by biopsy (25 cases by thoracoscopy, 1 by core needle aspiration). Twenty cases lay in anterior mediastinum, and 2 in posterior, 1 in superior, 8 in anterior and superior, 2 in posterior and superior, 2 in anterior and middle, 1 in middle and anterior mediastinum.Frozen section were performed in 28 cases, and 17 cases were diagnosed as tumours of haematopoietic and lymphoid tissues (consistency ratio was 60.7%). Twelve cases were classical Hodgkin lymphomas (cHL) (8 were nodular sclerosis subtype, and 3 were mixed cellarity, 1 was lymphocyte-rich subtype), and 10 were primary mediastinal (thymic) large B cell lymphoma (PMBCL), 10 were precursor lymphocyte neoplasm [8 were T lymphoblastic leukemia/lymphomas (T-LBL), 2 were B-LBL], 1 was MALT lymphoma, 1 was composite lymphoma (PMBCL and cHL), 2 were myeloid sarcomas, 4 were gray zone lymphomas (GZL) (3 had morphology reminiscent of cHL, and 1 of DLBCL, all cases were positive for CD20, PAX5, CD30 and CD15).EBER were detected in 11 cases by in situ hybridization, 2 of which were positive (18.2%), and the 2 positive cases were cHL.. MTHLs occur predominantly in adolescents and young adults, mainly present as superior vena cava syndrome and anterior mediasinal masses. cHL, PMBCL, T-LBL were the most common MTHLs.GZLs mainly occur in young adults, those whose morphology reminiscent of cHL, immunohistochemistry reminiscent of PMBCL, and vice versa. Thoracoscopy, frozen section and a suitable panel of antibodies were practical approaches to MTHL.

Topics: Adolescent; Adult; Aged; Antigens, CD20; Child; Female; Follow-Up Studies; Hodgkin Disease; Humans; Ki-1 Antigen; Lewis X Antigen; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Male; Mediastinal Neoplasms; Middle Aged; PAX5 Transcription Factor; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Superior Vena Cava Syndrome; Survival Rate; Young Adult

Programmed cell death, or apoptosis, is a physiological means of eliminating unwanted cells and maintaining immune homeostasis. One of the primary mechanisms is the Fas (CD95)/Fas ligand system. Its inactivation in normal cells and malignant cells may be involved in malignant trans-formation and refractory clinical course, respectively. We established a Fas resistant clone and evaluated the molecular basis for its mechanism of resistance. The Fas-sensitive leukemia cell line, MML-1, was established from a child with B-precursor acute lymphoblastic leukemia. A Fas resistant clone, MML-1R, was obtained by co-culture selection with anti-Fas antibody CH-11. Flow cytometry analysis showed both cell lines had equivalent expression of cell surface CD13, 15, 19, 22 and Fas receptor. Western blot analysis revealed equal expression of FADD (Fas-associated death domain protein), caspase-3 and -8. MML-1 was quite sensitive to both CH-11 and etoposide-induced apoptotis. By contrast, MML-1R had similar sensitivity to etoposide but no response to CH-11. Fas receptor mutation analysis showed a heterozygous death domain A --> G point mutation at 1009 bp, causing a switch from glutamine to glycine at amino acid 256. Immunoprecipitation assay showed decreased binding of Fas to FADD. We also found that etoposide bypassed Fas-FADD interaction in MML-1R by activating caspase-8 and caspase-3. These results indicate that Fas resistance can result from mutations of the gene encoding the Fas receptor which result in decreased FADD binding, thereby blocking formation of the death inducing signaling complex. Screening for similar Fas mutations in therapy resistant malignancies would lead to a better understanding of tumorigenesis and recurrence.

Topics: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Antibodies, Monoclonal; Antigens, CD19; Antineoplastic Agents, Phytogenic; Apoptosis; Base Sequence; Blotting, Western; Caspase 3; Caspase 8; Caspases; Cell Line, Tumor; Child; DNA Mutational Analysis; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Activation; Etoposide; fas Receptor; Fas-Associated Death Domain Protein; Flow Cytometry; Humans; Lewis X Antigen; Mutation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Binding

Expression mechanism of CD15s (sialyl-Lex, sLex) antigen has been investigated using human B lymphoid cell lines. sLexstructures were not expressed in mature B lymphoids but highly expressed in pre-B leukemia and pre-B lymphoma cell lines. The expression site was mainly on the O -linked oligosaccharide chains and E-selectin mediated-cell adhesion capability of sLex-positive cells were significantly suppressed by benzyl-alpha-GalNAc treatment. Subsequently, the bases of the sLexexpression control mechanism were examined at the levels of enzymatic activities and transcripts of glycosyltransferases. (1) The activities of alpha1-->3fucosyltransferase, alpha2-->3sialyltransferase, beta1-->4Gal-transferase, and elongation beta1-->3GlcNAc-transferase, did not correlate with sLexexpression levels. (2) The transcripts of Fuc-TVII were not parallel with sLexexpression, and those of ST3Gal IV and beta1-->4Gal-transferase were constitutively detected in all cell lines tested. (3) There was no detectable enzyme activity for core 3 and 4 backbone structure synthesis in human B cell lines. (4) By contrast, the enzyme activities and transcripts of UDP-GlcNAc:Galbeta1-->3GalNAc (GlcNAc to GalNAc) beta1-->6 N -acetylglucosaminyltransferase (Core2GnT) had significant correlation with the cell surface expression of sLexantigen. (5) Moreover, Western blot analysis revealed the presence of a major approximately 150 kDa glycoprotein that carries O -linked oligosaccharides recognized by anti-sLexmonoclonal antibody in sLex-positive pre-B leukemia cell lines. This correlation of Core2GnT with CD15s expression suggests that Core2GnT is a regulator of the cell surface expression of sLexin human pre-B lymphoid cells.

Topics: Antigens, CD; B-Lymphocytes; Carbohydrate Conformation; Carbohydrate Sequence; Cell Adhesion; E-Selectin; Gene Expression; Humans; Hyaluronan Receptors; Leukosialin; Lewis X Antigen; Molecular Sequence Data; N-Acetylglucosaminyltransferases; Oligosaccharides; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Reverse Transcriptase Polymerase Chain Reaction; Sialoglycoproteins; Transfection; Tumor Cells, Cultured

The t(4;11)(q21;q23) characterizes a distinct clinical entity of childhood and adult acute lymphoblastic leukemia (ALL) with a pre-pre-B-phenotype, monocytoid features, coexpression of CD15 and/or CDw65 and a dismal prognosis. The molecular correlate of the t(4;11) has been identified as a fusion transcript of HRX, a gene on 11q23 with homology to drosophila trithorax gene, and FEL, a serine-proline-rich gene on 4q21 of unknown function. The aim of the current study was to establish a reverse transcription-polymerase chain reaction (RT-PCR) approach for the rapid and sensitive detection of the HRX-FEL fusion transcript associated with the t(4;11). For this purpose, two groups of patients were studied: group A comprised cases with cytogenetically proven t(4;11) including three infant and four adult pre-pre-B-ALL, as well as the two cell lines RS4;11 and MV4;11. Group B consisted of ten adult pre-pre-B-ALL with the identical phenotype, but without cytogenetic confirmation of t(4;11). Using primers complementary to HRX and FEL cDNA sequences 300 to 500 bp 5' and 3' of published breakpoints, respectively, specific amplification products were obtained in all nine cases of group A and in nine of the ten cases of group B. Three different types of fusion transcripts were identified by sequence analysis with HRX breakpoints at nucleotides 4086 and 4218 and FEL breakpoints at nucleotides 1413, 1416, and 1458. These data indicate that RT-PCR allows the detection of HRX-FEL fusion transcripts in the vast majority of cytogenetically proven and immunophenotypically suspected t(4;11) ALL. Hence, this technique may allow identification of a further subset of high risk ALL and may also be useful for the monitoring of minimal residual disease in t(4;11) ALL.

Topics: Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Neoplasm; Base Sequence; Child; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 4; Humans; Lewis X Antigen; Molecular Sequence Data; Neoplasm Proteins; Polymerase Chain Reaction; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Translocation, Genetic

The prognostic significance of expression of myeloid-associated antigens in childhood acute lymphoblastic leukemia (myA+ALL) was evaluated. From 1984 to 1990, 251 children with immunologically verified ALL were treated in two prospective consecutive Austrian studies. Complete immunophenotyping was performed in 206 cases (82%). Out of these 175 cases were classified as B-cell precursor ALL, 31 cases as T-ALL. Expression of myeloid-associated antigens was demonstrated in 23 cases (13.1%) of childhood B-cell precursor ALL, particularly in immature (CD10 negative) forms (P < .0001), and in 1 case (3.2%) of T-ALL. CDw65 was expressed most frequently (12 cases), followed by CD13 and CD15 (5 cases each), CD33 (4 cases), and blood-group H (3 cases). Compared to myA- ALL prognosis of children with myA+ B-cell precursor ALL was poor, despite intensive multiagent chemotherapy according to BFM protocols. Remission rates were not impaired, but pEFS was 74.6% for myA- ALL, and only 37.8% for myA+ ALL (P = .0001). As demonstrated by multivariate analysis the expression of myeloid-associated antigens was the most important prognostic variable for EFS in B-cell precursor ALL, whether or not CD10 was expressed.

Topics: Adolescent; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Child; Cranial Irradiation; Hemoglobins; Humans; Immunophenotyping; Leukemia-Lymphoma, Adult T-Cell; Leukocytes; Lewis X Antigen; Multivariate Analysis; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Prognosis; Prospective Studies; Treatment Outcome

Pre-B acute lymphoblastic leukemia (ALL) was diagnosed in 37 children morphologically, histochemically, and by immunophenotyping by flow cytometry. In all patients the leukemic blasts expressed HLA-DR and CD19 (Leu-12). In 10 patients 20% or more of the blast cells expressed a myeloid antigen: CD15 (Leu-M1) in seven, CD33 (My9) in two and CD13 (My7) in one patient. All 37 children achieved complete remission, but eight relapsed. Relapse occurred in six of seven patients with CD15-positive blasts, but in only two of 27 patients with CD15-negative blasts (p = 0.0003). Thus, the occurrence of CD15 on the blasts of children with pre-B ALL shows a remarkable association with a high risk of relapse, and these patients should therefore be considered to belong to the high-risk group regardless of other prognostic factors.

Topics: Adolescent; Antigens, CD; Antigens, Differentiation; Antigens, Differentiation, Myelomonocytic; Antigens, Neoplasm; Child; Child, Preschool; Female; Humans; Immunophenotyping; Infant; Infant, Newborn; Lewis X Antigen; Male; Neprilysin; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis