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Systematic genomic screen for tyrosine kinase mutations in CLL

Leukemia volume 22, pages 1966–1969 (2008)Cite this article

Increasing data suggest that activating kinase mutations are important in chronic and acute hematologic malignancies. The prototypical example is the BCR-ABL kinase that is activated in chronic myelogenous leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia (ALL), but activating kinase mutations have also been identified in chronic myelomonocytic leukemia, chronic eosinophilic leukemia and systemic mastocytosis. Circumstantial evidence suggests that gain-of-function tyrosine kinase alleles could also contribute to the pathogenesis of chronic lymphocytic leukemia (CLL). Microarray studies of gene expression differences between steadily progressive CLLs that lack somatic hypermutation of the immunoglobulin heavy chain variable gene region (IgVH unmutated) and more indolent IgVH-mutated CLLs have found that many of the differentially expressed genes are involved in B-cell receptor signaling, most notably the ZAP-70 tyrosine kinase. Other kinases found to be overexpressed in CLL by gene expression studies include BLK, JAK2, LYN, and NTRK3, although mutational analysis of these genes in CLL has been limited. The goal of this project was therefore to search systematically for activating mutations in protein tyrosine kinases in CLL using high-throughput DNA resequencing.

A total of 178 exons were sequenced from each of 95 patients. The patients were selected to encompass the range of prognostic groups defined by IgVH homology, ZAP-70 expression and FISH cytogenetics. IgVH homology (unmutated defined as greater than or equal to 98% homology to the closest germline match) and ZAP-70 expression (positive defined as >20%) were determined by the CLL Research Consortium tissue core as previously described,1 and cytogenetics were evaluated by FISH for the most common abnormalities (del 13q, trisomy 12, del 11q, del 17p, chromosome 14 rearrangements) at Dana-Farber Cancer Institute (Boston, MA).2 Although the CLL cases studied showed some bias toward lower risk features (IgVH-mutated 56%, unmutated 28%, ND 16%; ZAP70 negative 52%, positive 24%, ND 24%; CD38 negative (<30%) 70%, positive 24%, ND 6%), nonetheless both high- and low-risk patients of each type were included in the study. Similarly, the common cytogenetic features of CLL were well represented, including 38% with only del 13q, 7% normal, 17% with del 11q, 21% with del 17p and 8% with complex cytogenetics (see Supplementary Table 1 for a complete list). A total of 15.6% of these patients reported a family history of CLL, non-Hodgkin's lymphoma or Hodgkin's disease, which is comparable to the rate in our general clinic population.3 Thus, the patient population studied encompassed the full spectrum of biologic variability in CLL.

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Acknowledgements

This work was supported in part by NIH grants K23 CA115682 to JRB, a Friends of Dana-Farber Cancer Institute award to JRB, and a Dunkin Donuts Rising Stars Program award to JRB. RLL is a Basic Research Fellow of the American Society of Hematology. DGG is supported in part by NIH grant CA66996 and the Leukemia and Lymphoma Society. ASF is supported in part by NIH grant 2P01CA092625. We thank the CLL Research Consortium Tissue Core for the data on IgVH mutational status and ZAP-70 expression.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    J R Brown, R L Levine, C Thompson, G Basile, D G Gilliland & A S Freedman

  2. Department of Medicine, Harvard Medical School, Boston, MA, USA

    J R Brown, R L Levine, D G Gilliland & A S Freedman

  3. Division of Hematology, Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA

    R L Levine & D G Gilliland

  4. Howard Hughes Medical Institute, Boston, MA, USA

    D G Gilliland

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  1. J R Brown
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  2. R L Levine
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  3. C Thompson
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  4. G Basile
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Correspondence to J R Brown.

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

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Brown, J., Levine, R., Thompson, C. et al. Systematic genomic screen for tyrosine kinase mutations in CLL. Leukemia 22, 1966–1969 (2008). https://doi.org/10.1038/leu.2008.222

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