Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation.
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.
Rodríguez
A
A
Molecular Pathology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Villuendas
R
R
Yáñez
L
L
Gómez
M E
ME
Díaz
R
R
Pollán
M
M
Hernández
N
N
de la Cueva
P
P
Marín
M C
MC
Swat
A
A
Ruiz
E
E
Cuadrado
M A
MA
Conde
E
E
Lombardía
L
L
Cifuentes
F
F
Gonzalez
M
M
García-Marco
J A
JA
Piris
M A
MA
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*
D016328:NF-kappa B; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr