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Cellular and molecular analysis tools for lymphoma and leukemia diagnosis

Current diagnosis of hematologic diseases like lymphomas or acute leukemias is based on a synthesis of various laboratory technologies: morphologic analyses using microscopes, immunophenotype analyses using flow cytometry, chromosome analyses using caryotyping and FISH, as well as genetic analyses using molecular biology techniques. In our group we develop new molecular methods for a better and more precise classification of leukemias and lymphomas.

Project 1: Leukemia and lymphoma diagnosis using nanotechnology

During the last ten years gene expression profiling (GEP) using microarray technology has emerged as a powerful method for better classification of disease entities, outcome prediction, pathway delineation, and identification of targets for therapeutic intervention in various haematological malignancies. In our project we establish prediction algorithms for the diagnosis and classification of acute leukemias and of B cell lymphomas using a new mRNA profiling system, more sensitive and precise than traditionnal microarrays, in combination with new mathematical analysis tools. In collaboration with a group at the Haute Ecole HEIG-VD at Yverdon we are developing supervised and non-supervised approaches based on fuzzy logic, in order to optimize the classification process for each patient.

Project 2: Leukemia and lymphoma diagnosis using High-throughput sequencing

With the advent of next-generation sequencing (NGS) methods the possibilities of analyzing the human genome have dramatically changed. As this technology is improving constantly and the cost decrease, analyzing patient samples becomes accessible to more and more laboratories and it can be foreseen that in the future NGS sequencing will allow to determine genomic alterations in unprecedented detail and precision, not only in diseases due to germline mutations, but as well in somatically acquired diseases and in particular in tumors. Sequencing a genome from a tumor cell presents nevertheless some difficulties (size and state of a sample, ploidy, clonal heterogeneity) and mutations are somatic and of a variable nature (point mutations, deletions, duplications, insertions/deletions, rearrangements,...), making it necessary to compare tumoral and constitutional genomes in a patient. Our project aims to develop NGS methods for leukemia, myelodysplastic syndrome and lymphoma samples using the capture technique to enrich for particular regions of the genome (transcription factors, cell cycle genes, apoptosis genes, adhesion molecules (see Point 3), ..), prior to sequencing.

Project 3: Analysis of the junctional adhesion molecule C (JAM-C) in normal and malignant B lymphocytes.

Junctional adhesion molecule C (JAM-C) is an adhesion molecule localized at the tight junction of cell/cell contacts. Among others, it is expressed in lymphatic organs, where it plays a role in the transendothelial migration of leucocytes. We have shown that this molecule is expressed on human B lymphocytes, and that its expression is restricted to precise differentiation steps in B cell maturation. Moreover, we have found that in B cell lymphomas JAM-C expression is disease-specific and thus constitutes a new marker for lymphoma diagnosis. We are currently investigating in a mouse model whether blocking JAM-C with anti-JAM-C antibodies or soluble ligands could inhibit B cell migration and lymphoma development in lymphoid organs and thus, whether targeting JAM-C could constitute a new therapeutic strategy, with JAM-C blocking as a treatment to prevent lymphoma cells from reaching supportive microenvironments in BM and spleen.

Group's publications

Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression.
PLOS ONE
2012 vol. 7(1) pp. 29979-29979
ALLANTAZ F AND AL.

Using digital RNA counting and flow cytometry to compare mRNA with protein expression in acute leukemias.
PLOS ONE
2012 vol. 7(11) pp. 49010-49010
FERNANDEZ P AND AL.

Production of the plasma-cell survival factor a proliferation-inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow.
BLOOD
2011 vol. 118(7) pp. 1838-1844
MATTHES T, DUNAND-SAUTHIER I, SANTIAGO-RABER ML, KRAUSE KH, DONZE O, PASSWEG J, MCKEE T, HUARD B

Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia.
HAEMATOLOGICA
2011 vol. 96(6) pp. 808-813
KANNENGIESSER C AND AL.

Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations.
HUMAN MUTATION
2011 vol. 32(6) pp. 590-597
DUCAMP S AND AL.

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells.
EUROPEAN JOURNAL OF IMMUNOLOGY
2010 vol. 40(9) pp. 2450-2459
RAMIREZ JM, BREMBILLA NC, SORG O, CHICHEPORTICHE R, MATTHES T, DAYER JM, SAURAT JH

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells.
EUROPEAN JOURNAL OF IMMUNOLOGY
2010 vol. 40(11) pp. 3246-3254
VUKICEVIC M, CHALANDON Y, HELG C, MATTHES T, DANTIN C, HUARD B, CHIZZOLINI C, PASSWEG J, ROOSNEK E

Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts
BRITISH JOURNAL OF HAEMATOLOGY
2009 vol. 144(2) pp. 251-262
RAMIREZ JM, SCHAAD O, DURUAL S, COSSALI D, DOCQUIER M, BERIS P, DESCOMBES P, MATTHES T

Tumors that look for their springtime in APRIL.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
2009 vol. 72(2) pp. 91-97
ROOSNEK E, BURJANADZE M, DIETRICH PY, MATTHES T, PASSWEG J, HUARD B

Fine-needle aspiration of the diffuse sclerosing variant of papillary thyroid carcinoma masked by florid lymphocytic thyroiditis; A potential pitfall
DIAGNOSTIC CYTOPATHOLOGY
2009 vol. 37(9) pp. 671-675
BONGIOVANNI M, TRIPONEZ F, MCKEE T, KUMAR N, MATTHES T, MEYER P

Intraplatform reproducibility and technical precision of gene expression profiling in 4 laboratories investigating 160 leukemia samples: the DACH study.
CLINICAL CHEMISTRY
2008 vol. 54(10) pp. 1705-1715
KOHLMANN A AND AL.

APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa.
JOURNAL OF CLINICAL INVESTIGATION
2008 vol. 118(8) pp. 2887-2895
HUARD B AND AL

Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness
BLOOD
2007 vol. 109(1) pp. 331-338
SCHWALLER J, SCHNEIDER P, MHAWECH-FAUCEGLIA P, MCKEE T, MYIT S, MATTHES T, TSCHOPP J, DONZE O, LE GAL FA, HUARD B

Molecular mechanism of hepcidin deficiency in a patient with juvenile hemochromatosis.
HAEMATOLOGICA
2007 vol. 92(1) pp. 127-128
RIDEAU A, MANGEAT B, MATTHES T, TRONO D, BERIS P

Junctional adhesion molecule C (JAM-C) distinguishes CD27+ germinal center B lymphocytes from non-germinal center cells and constitutes a new diagnostic tool for B-cell malignancies
LEUKEMIA
2007 vol. 21(6) pp. 1285-1293
ODY C, JUNGBLUT-RUAULT S, COSSALI D, BARNET M, AURRAND-LIONS M, IMHOF BA, MATTHES T

Lentiviral PU.1 overexpression restores differentiation in myeloid leukemic blasts
LEUKEMIA
2007 vol. 21(5) pp. 1050-1059
DURUAL S, RIDEAU A, RUAULT-JUNGBLUT S, COSSALI D, BERIS P, PIGUET V, MATTHES T

Paracrine promotion of tumor development by the TNF ligand APRIL in Hodgkin's Disease
LEUKEMIA
2007 vol. 21(6) pp. 1324-1327
SCHWALLER J, WENT P, MATTHES T, DIRNHOFER S, DONZE O, MHAWECH-FAUCEGLIA P, MYIT S, HUARD B

A follow-up: previously reported apparent lymphomatoid contact dermatitis, now followed by T-cell prolymphocytic leukaemia
BRITISH JOURNAL OF DERMATOLOGY
2006 vol. 155(3) pp. 633-634
ABRAHAM S, BRAUN RP, MATTHES T, SAURAT JH

Different pathophysiological mechanisms of intramitochondrial iron accumulation in acquired and congenital sideroblastic anemia caused by mitochondrial DNA deletion
EUROPEAN JOURNAL OF HAEMATOLOGY
2006 vol. 77(2) pp. 169-174
MATTHES T, RUSTIN P, TRACHSEL H, DARBELLAY R, COSTARIDOU S, XAIDARA A, RIDEAU A, BERIS P

Research's domains




DATABASE-RESEARCH	GROUP OF CLINICAL PATIENT RESEARCH

Prof. Thomas Matthes	Head of group CV	Research subject	Members of the group


	Links about the group Professeur Thomas Matthes HUG/Spécialités de Médecine Service d'Hématologie Rue Gabrielle-Perret-Gentil 4 1211 Genève 4 Suisse Thomas.Matthes@hcuge.ch Tel.: +41 22 372 39 30 Comments Pages updated the 17.11.2015		Reseach's subject \| Group's publications \| Research's domains Cellular and molecular analysis tools for lymphoma and leukemia diagnosis Current diagnosis of hematologic diseases like lymphomas or acute leukemias is based on a synthesis of various laboratory technologies: morphologic analyses using microscopes, immunophenotype analyses using flow cytometry, chromosome analyses using caryotyping and FISH, as well as genetic analyses using molecular biology techniques. In our group we develop new molecular methods for a better and more precise classification of leukemias and lymphomas. Project 1: Leukemia and lymphoma diagnosis using nanotechnology During the last ten years gene expression profiling (GEP) using microarray technology has emerged as a powerful method for better classification of disease entities, outcome prediction, pathway delineation, and identification of targets for therapeutic intervention in various haematological malignancies. In our project we establish prediction algorithms for the diagnosis and classification of acute leukemias and of B cell lymphomas using a new mRNA profiling system, more sensitive and precise than traditionnal microarrays, in combination with new mathematical analysis tools. In collaboration with a group at the Haute Ecole HEIG-VD at Yverdon we are developing supervised and non-supervised approaches based on fuzzy logic, in order to optimize the classification process for each patient. Project 2: Leukemia and lymphoma diagnosis using High-throughput sequencing With the advent of next-generation sequencing (NGS) methods the possibilities of analyzing the human genome have dramatically changed. As this technology is improving constantly and the cost decrease, analyzing patient samples becomes accessible to more and more laboratories and it can be foreseen that in the future NGS sequencing will allow to determine genomic alterations in unprecedented detail and precision, not only in diseases due to germline mutations, but as well in somatically acquired diseases and in particular in tumors. Sequencing a genome from a tumor cell presents nevertheless some difficulties (size and state of a sample, ploidy, clonal heterogeneity) and mutations are somatic and of a variable nature (point mutations, deletions, duplications, insertions/deletions, rearrangements,...), making it necessary to compare tumoral and constitutional genomes in a patient. Our project aims to develop NGS methods for leukemia, myelodysplastic syndrome and lymphoma samples using the capture technique to enrich for particular regions of the genome (transcription factors, cell cycle genes, apoptosis genes, adhesion molecules (see Point 3), ..), prior to sequencing. Project 3: Analysis of the junctional adhesion molecule C (JAM-C) in normal and malignant B lymphocytes. Junctional adhesion molecule C (JAM-C) is an adhesion molecule localized at the tight junction of cell/cell contacts. Among others, it is expressed in lymphatic organs, where it plays a role in the transendothelial migration of leucocytes. We have shown that this molecule is expressed on human B lymphocytes, and that its expression is restricted to precise differentiation steps in B cell maturation. Moreover, we have found that in B cell lymphomas JAM-C expression is disease-specific and thus constitutes a new marker for lymphoma diagnosis. We are currently investigating in a mouse model whether blocking JAM-C with anti-JAM-C antibodies or soluble ligands could inhibit B cell migration and lymphoma development in lymphoid organs and thus, whether targeting JAM-C could constitute a new therapeutic strategy, with JAM-C blocking as a treatment to prevent lymphoma cells from reaching supportive microenvironments in BM and spleen. Group's publications Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression. PLOS ONE 2012 vol. 7(1) pp. 29979-29979 ALLANTAZ F AND AL. Using digital RNA counting and flow cytometry to compare mRNA with protein expression in acute leukemias. PLOS ONE 2012 vol. 7(11) pp. 49010-49010 FERNANDEZ P AND AL. Production of the plasma-cell survival factor a proliferation-inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow. BLOOD 2011 vol. 118(7) pp. 1838-1844 MATTHES T, DUNAND-SAUTHIER I, SANTIAGO-RABER ML, KRAUSE KH, DONZE O, PASSWEG J, MCKEE T, HUARD B Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia. HAEMATOLOGICA 2011 vol. 96(6) pp. 808-813 KANNENGIESSER C AND AL. Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations. HUMAN MUTATION 2011 vol. 32(6) pp. 590-597 DUCAMP S AND AL. Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. EUROPEAN JOURNAL OF IMMUNOLOGY 2010 vol. 40(9) pp. 2450-2459 RAMIREZ JM, BREMBILLA NC, SORG O, CHICHEPORTICHE R, MATTHES T, DAYER JM, SAURAT JH CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells. EUROPEAN JOURNAL OF IMMUNOLOGY 2010 vol. 40(11) pp. 3246-3254 VUKICEVIC M, CHALANDON Y, HELG C, MATTHES T, DANTIN C, HUARD B, CHIZZOLINI C, PASSWEG J, ROOSNEK E Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts BRITISH JOURNAL OF HAEMATOLOGY 2009 vol. 144(2) pp. 251-262 RAMIREZ JM, SCHAAD O, DURUAL S, COSSALI D, DOCQUIER M, BERIS P, DESCOMBES P, MATTHES T Tumors that look for their springtime in APRIL. CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY 2009 vol. 72(2) pp. 91-97 ROOSNEK E, BURJANADZE M, DIETRICH PY, MATTHES T, PASSWEG J, HUARD B Fine-needle aspiration of the diffuse sclerosing variant of papillary thyroid carcinoma masked by florid lymphocytic thyroiditis; A potential pitfall DIAGNOSTIC CYTOPATHOLOGY 2009 vol. 37(9) pp. 671-675 BONGIOVANNI M, TRIPONEZ F, MCKEE T, KUMAR N, MATTHES T, MEYER P Intraplatform reproducibility and technical precision of gene expression profiling in 4 laboratories investigating 160 leukemia samples: the DACH study. CLINICAL CHEMISTRY 2008 vol. 54(10) pp. 1705-1715 KOHLMANN A AND AL. APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa. JOURNAL OF CLINICAL INVESTIGATION 2008 vol. 118(8) pp. 2887-2895 HUARD B AND AL Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness BLOOD 2007 vol. 109(1) pp. 331-338 SCHWALLER J, SCHNEIDER P, MHAWECH-FAUCEGLIA P, MCKEE T, MYIT S, MATTHES T, TSCHOPP J, DONZE O, LE GAL FA, HUARD B Molecular mechanism of hepcidin deficiency in a patient with juvenile hemochromatosis. HAEMATOLOGICA 2007 vol. 92(1) pp. 127-128 RIDEAU A, MANGEAT B, MATTHES T, TRONO D, BERIS P Junctional adhesion molecule C (JAM-C) distinguishes CD27+ germinal center B lymphocytes from non-germinal center cells and constitutes a new diagnostic tool for B-cell malignancies LEUKEMIA 2007 vol. 21(6) pp. 1285-1293 ODY C, JUNGBLUT-RUAULT S, COSSALI D, BARNET M, AURRAND-LIONS M, IMHOF BA, MATTHES T Lentiviral PU.1 overexpression restores differentiation in myeloid leukemic blasts LEUKEMIA 2007 vol. 21(5) pp. 1050-1059 DURUAL S, RIDEAU A, RUAULT-JUNGBLUT S, COSSALI D, BERIS P, PIGUET V, MATTHES T Paracrine promotion of tumor development by the TNF ligand APRIL in Hodgkin's Disease LEUKEMIA 2007 vol. 21(6) pp. 1324-1327 SCHWALLER J, WENT P, MATTHES T, DIRNHOFER S, DONZE O, MHAWECH-FAUCEGLIA P, MYIT S, HUARD B A follow-up: previously reported apparent lymphomatoid contact dermatitis, now followed by T-cell prolymphocytic leukaemia BRITISH JOURNAL OF DERMATOLOGY 2006 vol. 155(3) pp. 633-634 ABRAHAM S, BRAUN RP, MATTHES T, SAURAT JH Different pathophysiological mechanisms of intramitochondrial iron accumulation in acquired and congenital sideroblastic anemia caused by mitochondrial DNA deletion EUROPEAN JOURNAL OF HAEMATOLOGY 2006 vol. 77(2) pp. 169-174 MATTHES T, RUSTIN P, TRACHSEL H, DARBELLAY R, COSTARIDOU S, XAIDARA A, RIDEAU A, BERIS P Research's domains