{'fraction_non_alphanumeric': 0.0315180102915952, 'fraction_numerical': 0.02144082332761578, 'mean_word_length': 5.43448275862069, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Role of the microenvironment in chronic lymphocytic leukaemia

In several B-cell malignancies the microenvironment confers a growth advantage and extended survival to malignant B cells. In chronic lymphocytic leukaemia three issues need to be resolved. First, to determine whether the microenvironment favours the development of the disease, promotes its progression or is involved in both events. Secondly, to define the microenvironmental elements that influence the malignant clone and the relevant molecular pathways. Thirdly, to clarify how the microenvironment affects the relationships between proliferation and extended survival. A number of findings indirectly suggest that antigen stimulation within specific microenvironments may be involved in the genesis of the disease and indicate that critical malignant cell/microenvironment cross-talks may decisively influence the disease progression. T lymphocytes, mainly CD40Ligand, CD4 cells, as well as a variety of stromal cells, appear to have a central role in amplifying a microenvironment able to favour the proliferation within tissue pseudofollicles and to inhibit the apoptosis of malignant cells. B-cell chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world, diagnosed with increasing frequency in industrialized countries (Rozman & Montserrat, 1995) and is the prototype of B-cell chronic lymphoid malignancies CLL cells, that accumulate in peripheral blood (PB), express all the membrane markers of mature B lymphocytes, such as CD19, CD20, CD21, CD24, CD40, co-express CD5 and CD23 (reviewed by Caligaris-Cappio & Hamblin, 1999) and have a gene expression profile consistent with memory B cells (Klein et al, 2001; Rosenwald et al, 2001). Most circulating CLL lymphocytes are long-lived and arrested in the G0/early G1 phase of the cell cycle. They share with anergic B cells low to almost absent levels of surface immunoglobulins (sIg) and unresponsiveness to the conventional stimuli that promote the cell cycle progression of normal B cells (Caligaris-Cappio, 1996). Notwithstanding their resting state, PB CLL cells express membrane markers of cellular activation (Damle et al, 2002), have the mRNA for virtually all the cytokines investigated (Pistoia, 1997) and secrete several of them as activated B cells do (Caligaris-Cappio & Hamblin, 1999). In essence, PB CLL cells tend to be kinetically resting, phenotypically activated and functionally anergic. Three main issues are intermingled in the natural history of CLL. The analysis of IgVH gene sequences has revealed that the detection of somatic mutations is associated with a significantly longer median survival (Damle et al, 1999; Hamblin et al, 1999). The implication is that at least two molecularly recognizable distinct clinical entities (mutated and unmutated) are grouped under the name of CLL. There is a genetic predisposition and a familial tendency to develop CLL (Houlston et al, 2002). The gene(s) sustaining this predisposition and the gene(s) that underlie the primary transforming event(s) are unknown, while detailed cytogenetic studies are mapping with great accuracy a number of secondary genetic abnormalities that gradually render CLL more malignant (Dohner et al, 2000). Accordingly, the natural history of the disease is frequently prolonged, sometimes measurable in decades at least in the mutated group. The salient biological feature of CLL is the relentless in vivo accumulation of monoclonal B cells characterized by an extended survival in peripheral lymphoid organs, bone marrow (BM) and PB. Numerous investigations on the intrinsic ability of CLL cells to elude apoptosis (reviewed by Caligaris-Cappio & Hamblin, 1999 and Wickremasinghe & Hoffbrand, 1999) and quantitative assessment of apoptosisassociated molecules (Korz et al, 2002) have led to the notion that, irrespective of the rarity of the t(14;18) translocation, the Bcl-2 protein is consistently overexpressed in CLL cells when compared with CD19 B-cell fractions purified from normal donors. In addition, and again in the absence of known specific genetic abnormalities, the overall pattern of the BCL-2 gene family expression is tuned to shield CLL cells from apoptosis (Caligaris-Cappio & Hamblin, 1999). These observations have turned the attention to extrinsic factors and suggested the possibility that an important role in favouring the extended survival of malignant cells might be played by the malignant cell capacity to respond to selected signals from the microenvironment (Ghia & Caligaris-Cappio, 2000) by upregulating Bcl-2 and other anti-apoptotic proteins such as Mcl-1 (Pedersen et al, 2002).