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The CLLU1 expression level is a stable and inherent feature of the chronic lymphocytic leukemia clone

Leukemia volume 23, pages 1182–1186 (2009)Cite this article

Although most leukemias harbor a common genetic aberration, useful for the classification and subgrouping of the disease, no common molecular event leading to chronic lymphocytic leukemia (CLL) has been described. CLLU1 was identified in a comparative screen of patients with and without somatic hypermutations in the variable region of their immunoglobulin receptor heavy chain genes (IgVH). The expression of CLLU1 was shown to be highly upregulated in patients without somatic hypermutations. Subsequent analysis showed that CLLU1 upregulation can be detected only in CLL cells, but not in any other tissue, cell line or in samples from patients with other hematological malignancies.1, 2 In earlier studies we found CLLU1 to have independent prognostic significance in CLL.3, 4 When CLLU1 was analyzed as a continuous variable, a doubling of the CLLU1 expression level was shown to be associated with an increase of 7% in the relative risk of early death.4 Others have since then confirmed the prognostic significance of CLLU1 in CLL.5, 6 The function of the CLLU1 gene is unknown. The gene is not conserved in other species and even though several of the CLLU1 splice variants contain a putative open reading frame of 121 amino acids, we have not yet been able to convincingly detect expression of the putative CLLU1 protein in CLL patient samples. Thus, we do not know whether CLLU1 plays a role in the pathogenesis of CLL, or whether its expression is a reflection of other events in the CLL cells.

To determine whether CLLU1 upregulation is a specific feature of CLL cells only, we isolated CD3+ cells (T cells) and CD19+ cells (B cells and CLL cells) from two CLL patient samples, and determined their CLLU1 expression level. In the first sample (UPN100), CLL cells constituted 96% of the CD19+-purified cells and the CLLU1 expression level was 218. T cells constituted 90% of the CD3+-selected sample and this sample had a CLLU1 expression value of 10.3. For UPN 600 the CD19-selected sample had 97% CLL cells and the CLLU1 expression level was 5239. In contrast, the T-cell population constituted 87% of the CD3-selected sample, which had a CLLU1 expression value of 74. These results suggest that expression of CLLU1 is restricted to the CLL cells. We subsequently identified 15 CLL patients, from whom blood and marrow samples were collected on the same date. The samples were Ficoll separated, and the CLLU1 expression levels were determined. Linear regression analysis showed that CLLU1 expression levels were similar in the paired blood and marrow samples (Figure 1c).

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Acknowledgements

This work was supported by grants from The Danish Cancer Society, The Danish Medical Research Council, The Alfred Benzon Foundation, Svend Andersen's Foundation, The Anders Hasselbalch Foundation, The Valdemar and Thyra Foersom Foundation and NIH grant PO1-CA081534. We are grateful to Brian V Hansen, Lone Bach, Trine C Larsen, Sabina Soultanova and Pernille T Sorensen for their technical assistance, and to Monica Cook and Danelle James for their assistance with database searches.

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Authors and Affiliations

  1. Department of Hematology, The Leukemia Laboratory, Rigshospitalet, Copenhagen, Denmark

    A M Buhl, P Josefsson, L B Pedersen, C Geisler & J Jurlander

  2. Division of Hematology/Oncology, Department of Medicine, University of California San Diego and the Moores UCSD Cancer Center, La Jolla, CA, USA

    A M Buhl, L Z Rassenti & T J Kipps

  3. University Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark

    G W Novotny, J E Nielsen & H Leffers

  4. The CLL Research Consortium, La Jolla, CA, USA

    L Z Rassenti & T J Kipps

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  1. A M Buhl
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  2. G W Novotny
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  3. P Josefsson
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  9. J Jurlander
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Correspondence to A M Buhl.

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

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Buhl, A., Novotny, G., Josefsson, P. et al. The CLLU1 expression level is a stable and inherent feature of the chronic lymphocytic leukemia clone. Leukemia 23, 1182–1186 (2009). https://doi.org/10.1038/leu.2009.16

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