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Chronic Lymphocytic Leukemia

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-κB1 (NF-κB1). 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-κB clusters, which can be used to predict time to treatment in early clinical stages.

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Acknowledgements

We thank the Tumour Bank Network of the CNIO for the coordination of shipment of samples. Francisco Cifuentes is a full-time employee of the company Agilent Technologies, whose custom product ‘8-pack microarray’ platform was used in the present study.

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Correspondence to M A Piris.

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Financial support: This study was supported by grants from the Ministerio de Sanidad y Consumo (G03/179, PI051623) and the Ministerio de Ciencia y Tecnología (SAF2005-00221, SAF2004-04286), Spain. Antonia Rodríguez was supported by a grant from the Asociación Española Contra el Cáncer (AECC).

Supplementary Information accompanies the paper on the Leukemia web site (http://www.nature.com/leu)

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Rodríguez, A., Villuendas, R., Yáñez, L. et al. Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation. Leukemia 21, 1984–1991 (2007). https://doi.org/10.1038/sj.leu.2404831

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