The Biology of the Disease Including Unanswered Questions

John Cawley
University of Liverpool

As its name implies, HCL is a leukaemia/lymphoma of malignant hairy cells (HCs). The number of HCs in the blood is very variable. When substantial numbers are present the disease resembles a leukaemia. When very few are found in the circulation, the disease more resembles a lymphoma involving the spleen and bone marrow.

Much, if not all, of the biology of HCL can be explained by the behaviour of the HCs themselves and by the reaction of tissues to the presence of the malignant cells.

The Hairy Cells

This descriptive name refers to the fact that the malignant cells of the disease have numerous surface projections or hairs; these hairs are the result of active reorganisation of the cytoskeleton.

This reorganisation is only one manifestation of the fact that HCs are highly activated memory B cells (lymphocytes making antibodies). Other features of activation include the diagnostic surface markers of the disease (CD11c, 25 & 103) and the constitutive activity of a number of signalling pathways (e.g. ERK responsible for cell survival and Rac responsible for surface hairs). Gene microarray data suggest that HCs are related to memory cells.

HCs and the Tissue Microenvironment

HCs have a particular propensity to home to spleen and bone marrow which they infiltrate and alter. In the spleen, the malignant cells often not only cause massive enlargement of the spleen, but also change its structure and function by obliterating the lymphoid areas and forming vascular lakes (known as pseudosinuses). In the bone marrow, the HCs often damage blood-cell production and also interact with a matrix component known as hyaluronan and this stimulates the HCs to produce protein known as fibronectin. This process produces the extensive bone marrow fibrosis which is an important diagnostic feature of HCL and which makes the bone marrow difficult to aspirate.

Unanswered Questions

The oncogenic event(s) responsible for the constitutive activation of HCs and for the differentiation block preventing further maturation beyond memory cells remain unknown. Identifying these oncogenic events remains the major remaining challenge concerning the biology of the disease.