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  • Review Article
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Evolving concepts in the pathogenesis of hairy-cell leukaemia

Nature Reviews Cancer volume 6, pages 437–448 (2006)Cite this article

Key Points

  • Hairy-cell leukaemia (HCL) is an indolent mature B-cell tumour of unknown genetic pathogenesis. Neoplastic cells have hair-like surface projections, infiltrate the bone marrow, the spleen and the liver, and circulate in low numbers in peripheral blood. Unlike other B-cell malignancies, HCL does not consistently involve the lymph nodes, does not bear chromosomal translocations and is highly sensitive to treatment with interferon-α (IFNα) and purine analogues.

  • The normal B-cell counterpart of HCL is still debated. However, its genome-wide expression signature and its mutated immunoglobulin genes suggest that HCL is derived from memory B cells, possibly from the splenic marginal zone (SMZ).

  • Clonal expansion is largely the result of increased cell survival rather than proliferation. The growth properties of HCL are regulated by intracellular signalling pathways (including mitogen activated protein kinase (MAPK) cascades) and autocrine loops (including tumour necrosis factor-α (TNFα)–TNF receptors (TNFRs)), with the microenvironment providing important pro-survival signals.

  • HCL cells home to, and remain in, blood-related compartments (bone marrow, spleen and hepatic sinusoids) through their activated integrin receptors and, probably, through the overexpression of matrix-metalloproteinase inhibitors. Conversely, chemokine receptors and adhesion proteins that are crucial for homing to the lymph nodes are downregulated.

  • Another unusual feature of HCL is bone-marrow fibrosis. Tumour cells secrete the fibrogenic cytokines basic fibroblast growth factor (bFGF) and tumour growth factor β1 (TGFβ1), which trigger the production of a fibronectin matrix by leukaemic cells and type III collagen fibres by fibroblasts, respectively.

  • 'Hairy' morphology might increase the cell surface area available for interaction with the microenvironment. Rho GTPases shape the membrane and the actin-rich cytoskeleton of HCL cells, probably with a contribution from other proteins such as pp52, growth arrest specific 7 (GAS7) and EPB4.1L2.

  • HCL-like disorders (HCL-variant (HCLv) and splenic lymphoma with villous lymphocytes (SLVL)) also present with splenomegaly, circulating 'hairy' cells and infrequent lymph node involvement, but do not respond to IFNα and purine analogues. Annexin-1 is a highly sensitive and specific HCL marker, helping in this crucial diagnostic step.

  • In the future, elucidation of the key genetic lesions and molecular factors responsible for HCL development should lead to new, specific and less immunnosuppressive drugs.

Abstract

Hairy-cell leukaemia (HCL) has long been recognized as distinct from other chronic B-cell malignancies, but several questions remain unanswered. What is the HCL cell of origin? Why does HCL lack the hallmarks of most mature B-cell tumours (for example, chromosomal translocations and consistent lymph node involvement) and show unique features like 'hairy' morphology and bone-marrow fibrosis? Gene-expression profiling and other studies have recently provided new insights into HCL biology and have the potential to affect clinical practice.

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Figure 1: Morphology of hairy cells.
Figure 2: Signalling pathways involved in hairy-cell leukaemia (HCL) growth.
Figure 3: Hairy-cell leukaemia (HCL) homing and dissemination properties.
Figure 4: 'Hairy' morphology: molecular mediators and their relationship with hairy-cell survival.

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Acknowledgements

This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to B. Falini. E. Tiacci was supported by a fellowship from L. Benedetti. We thank R. Küppers for helpful discussions and comments and G. Boyd for assistance in editing the manuscript.

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Authors and Affiliations

  1. Institute of Haematology, University of Perugia, Italy

    Enrico Tiacci & Brunangelo Falini

  2. Institute for Cell Biology Tumour Research, University of Duisburg-Essen, Medical School, Essen, Germany

    Enrico Tiacci

  3. Institute of Haematology, University of Foggia, Italy

    Arcangelo Liso

  4. Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain

    Miguel Piris

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  1. Enrico Tiacci
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  4. Brunangelo Falini
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Correspondence to Enrico Tiacci or Brunangelo Falini.

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Glossary

Pancytopaenia

A reduction in the number of all three blood-cell lineages; that is, red cells, white cells and platelets. In HCL, this is usually the result of bone-marrow failure (caused by leukaemic infiltration) combined with increased blood-cell destruction by the enlarged spleen (hypersplenism).

Splenomegaly

The enlargement of the spleen. It can be measured by physical examination and/or other procedures, such as ultrasound or computer tomography (CT)-scans.

Immunoglobulin

The Ig, or antibody, is the main component of the Bcell receptor, which is expressed by all B cells. An Ig consists of variable (V) regions, which interact with the antigen, and a constant (C) region, which mediates the effector function of the Ig.

Splenic marginal zone

An area rich in B cells that lies between the lymphoid follicle and the red pulp in the spleen, and that is not usually observed in lymph nodes. Marginal zone B-cells include post-GC memory B cells, and B cells that are implicated in Tcell independent antigenic responses.

Comparative expressed sequence hybridization

A recently introduced technique that identifies chromosomal regions corresponding to a differential gene expression. This technique is analogous to comparative genomic hybridization that detects genomic imbalances.

Spleen structure

There are two main compartments in the splenic parenchyma (called pulp): the red pulp (made up of splenic sinusoids and cords) and the white pulp (made up of small round structures of lymphoid tissue).

Hepatic sinusoids

Small vascular channels where blood from the portal vein and hepatic artery mixes together. They are lined with highly-fenestrated (full of holes) endothelium and bound around the circumference by hepatocytes. Specialized phagocytic macrophages (Kpfer's cells) are associated with sinusoids.

Splenic sinusoids

Splenic sinusoids are large, irregular, thin-walled blood vessels that are interposed between sheets and strands of reticular connective tissue, the so-called splenic cords (or Billroth's cords). They are the main constituents of the splenic red pulp.

Splenic pseudosinuses

HCL-associated lesions consisting of prominent distended spaces resembling dilated sinuses that are lined by HCL cells and filled with erythocytes.

Hepatic angiomatous lesions

HCL-associated lesions like splenic pseudosinuses that have a hemangioma-like appearance.

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Tiacci, E., Liso, A., Piris, M. et al. Evolving concepts in the pathogenesis of hairy-cell leukaemia. Nat Rev Cancer 6, 437–448 (2006). https://doi.org/10.1038/nrc1888

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