title: Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation.
abstract: Chronic lymphocytic leukemia (CLL), the most frequent form of adult leukemia in Western countries, is characterized by a highly variable clinical course. Expression profiling of a series of 160 CLL patients allowed interrogating the genes presumably playing a role in pathogenesis, relating the expression of functionally relevant signatures with the time to treatment. First, we identified genes relevant to the biology and prognosis of CLL to build a CLL disease-specific oligonucleotide microarray. Second, we hybridized a training series on the CLL-specific chip, generating a biology-based predictive model. Finally, this model was validated in a new CLL series. Clinical variability in CLL is related with the expression of two gene clusters, associated with B-cell receptor (BCR) signaling and mitogen-activated protein kinase (MAPK) activation, including nuclear factor-kappaB1 (NF-kappaB1). The expression of these clusters identifies three risk-score groups with treatment-free survival probabilities at 5 years of 83, 50 and 17%. This molecular predictor can be applied to early clinical stages of CLL. This signature is related to immunoglobulin variable region somatic hypermutation and surrogate markers. There is a molecular heterogeneity in CLL, dependent on the expression of genes defining BCR and MAPK/NF-kappaB clusters, which can be used to predict time to treatment in early clinical stages.
authors.affiliation: Molecular Pathology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez
authors.forename: R
authors.initials: R
authors.lastname: Villuendas
authors.forename: L
authors.initials: L
authors.lastname: Yáñez
authors.forename: M E
authors.initials: ME
authors.lastname: Gómez
authors.forename: R
authors.initials: R
authors.lastname: Díaz
authors.forename: M
authors.initials: M
authors.lastname: Pollán
authors.forename: N
authors.initials: N
authors.lastname: Hernández
authors.forename: P
authors.initials: P
authors.lastname: de la Cueva
authors.forename: M C
authors.initials: MC
authors.lastname: Marín
authors.forename: A
authors.initials: A
authors.lastname: Swat
authors.forename: E
authors.initials: E
authors.lastname: Ruiz
authors.forename: M A
authors.initials: MA
authors.lastname: Cuadrado
authors.forename: E
authors.initials: E
authors.lastname: Conde
authors.forename: L
authors.initials: L
authors.lastname: Lombardía
authors.forename: F
authors.initials: F
authors.lastname: Cifuentes
authors.forename: M
authors.initials: M
authors.lastname: Gonzalez
authors.forename: J A
authors.initials: JA
authors.lastname: García-Marco
authors.forename: M A
authors.initials: MA
authors.lastname: Piris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018740:Genetic Heterogeneity; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008875:Middle Aged; D005810:Multigene Family; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr