1. ¹Molecular Pathology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
2. ²Hematology Department, Hospital Marqués de Valdecilla, Santander, Spain
3. ³Hematology Department, Hospital Gregorio Marañón, Madrid, Spain
4. ⁴Bioinformatic Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
5. ⁵National Centre for Epidemiology, Carlos III Institute of Health, Madrid, Spain
6. ⁶Genetics and Pathology Department, Hospital Virgen de la Salud, Toledo, Spain
7. ⁷Biotechnology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
8. ⁸Agilent Technologies, Palo Alto, CA, USA
9. ⁹Hematology Department, Hospital Clínico Universitario, Salamanca, Spain
10. ¹⁰Hematology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain

Correspondence: Dr MA Piris, Molecular Pathology Program, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain. E-mail: mapiris@cnio.es

Received 12 December 2006; Revised 28 May 2007; Accepted 30 May 2007; Published online 5 July 2007.

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-B1 (NF-B1). 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-B clusters, which can be used to predict time to treatment in early clinical stages.