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HS1 complexes with cytoskeleton adapters in normal and malignant chronic lymphocytic leukemia B cells

Leukemia volume 21, pages 2067–2070 (2007)Cite this article

Hematopoietic cell-specific Lyn substrate 1 (HS1, HCLS1, LckBP1) is a 75-kDa intracellular protein expressed in cells of lymphohemopoietic origin. It was originally identified in B-lymphocytes as a major substrate of B-cell receptor (BCR)-induced phosphorylation after antigen (Ag) stimulation. Genetically modified mice confirmed that in both B and T-lymphocytes HS1 is involved in the processes of Ag-receptor-induced clonal expansion and deletion.1 However, the specific role of HS1 remained elusive. Previous studies were not unequivocal, as they suggested various possibilities including actin-binding activity, involvement in apoptosis and a nuclear function. Likewise, the subcellular localization is unclear, as HS1 was reported to be inside the nucleus, in the cytoplasm and in the lipid rafts of B-lymphocytes. The analysis of the amino-acid sequence showed that HS1 has a modular structure and is structurally related to cortactin, a cortical actin-associated protein that modulates the dynamics of the actin cytoskeleton. This structural relationship is underscored by the existence of a putative actin-binding domain at the N-terminus of HS1 molecule. Accordingly, it has been shown recently that in T-lymphocytes HS1 appears to play a non-redundant role as an actin-regulator at the immunological synapse.2

We aimed at elucidating the subcellular localization and function of HS1 in B cells by taking advantage of our observation that HS1 is differentially expressed in distinct subsets of patients with chronic lymphocytic leukemia (CLL),3 a malignancy characterized by the relentless accumulation of mature B cells in the peripheral blood, bone marrow and peripheral lymphoid organs. CLL cases with an aggressive behavior are characterized by the prominent expression of the phosphorylated form of HS1 while those with an indolent course tend to have HS1 mainly in the unphosphorylated form. This finding goes along the vein indicated by several studies of CLL BCR, which raise the possibility that an antigenic drive may play a role in the selection and expansion of the malignant clone. These observations are corroborated by the notion that CLL cells may show the expression of gene products associated with B-cell signaling and activation. One example is CD38, a signaling molecule that may influence the outcome of BCR signaling; another is the expression of the zeta chain-associated protein of 70 kDa (ZAP-70), a kinase that shares functions with the tyrosine kinase SYK.

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Acknowledgements

This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the CLL Global Research Foundation and the Ministero dell’Istruzione dell’Università e della Ricerca (MIUR 2005 069432004). CS is recipient of a fellowship from ‘Fondazione Anna Villa e Felice Rusconi’. We are grateful to Rose Mary Carletti for her valuable technical assistance and to Annalisa Camporeale and Claudia Fazi for their continuous support in the lab. We thank Rossano Cesari for his precious help for real time analysis and professor Marchisio for helpful suggestions and support with microscopy. We also thank all colleagues working in the Mass Spectrometry Unit and the Proteome Biochemistry Unit at the San Raffaele Institute for their friendly and collaborative support.

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Author notes

  1. M Muzio and C Scielzo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Lymphoid Malignancies Unit, Università Vita-Salute San Raffaele and San Raffaele Scientific Institute Milan, Italy

    M Muzio, C Scielzo, M Frenquelli, P Ghia & F Caligaris-Cappio

  2. Mass Spectrometry Unit, San Raffaele Scientific Institute, Milan, Italy

    A Bachi

  3. Telethon Institute for Gene Therapy and Angiogenesis and Tumor Targeting Research Unit, San Raffaele Scientific Institute, Milan, Italy

    M De Palma

  4. Proteome Biochemistry Unit, San Raffaele Scientific Institute, Milan, Italy. E-mail: caligaris.federico@hsr.it,

    M Alessio

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

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Muzio, M., Scielzo, C., Frenquelli, M. et al. HS1 complexes with cytoskeleton adapters in normal and malignant chronic lymphocytic leukemia B cells. Leukemia 21, 2067–2070 (2007). https://doi.org/10.1038/sj.leu.2404744

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