Chronic lymphocytic leukaemia: the nature of the leukaemic cell

doi:10.1016/S0268-960X(97)90007-2

Blood Reviews

Volume 11, Issue 3, September 1997, Pages 119-128

https://doi.org/10.1016/S0268-960X(97)90007-2 Get rights and content

Abstract

Far from being the boring, inactive, inert lymphocyte that haematologists of old perceived it to be, the chronic lymphocytic leukaemia (CLL) cell has set us many complex problems. The cell is apparently stuck in G₀ in cell cycle, yet expresses many activation markers. The cells apparently manufacture many cytokines and respond in vitro to even more, yet cells entering even G₁ are few. The cell surface marker profile is unique. There is apparently no normal equivalent of the CLL cell. In part, this may be because the cell is malignant; malignant cells often express aberrant markers. Consistent chromosomal abnormalities are emerging but we have no idea how these abnormalities translate into molecular mistakes that dictate the peculiar nature of the cell. CLL cells carry a characteristic set of adhesion molecules, but we cannot read their homing and recycling instructions. The outstanding irregularities of the CLL cell are its CDS positivity and its sparse surface immunoglobulin. This ought to translate as an anergic B 1 cell, perhaps programmed for autoimmunity. If the tumour cell were responsible for the patient's production of immunoglobulin or secretion of autoantibodies, then a pattern might have emerged. Alas, these are the product of the normal B cells. How the CLL cell induces these complications is unknown. Thus, despite the information contained in this review, the CLL cell remains a puzzle.

References (123)

M. Andreeff et al.
Discrimination of human leukemia subtypes by flow cytometric analysis of cellular DNA and RNA
Blood
(1980)
A. Delmer et al.
Overexpression of Cyclin D2 in chronic B-cell malignancies
Blood
(1995)
J. Okamura et al.
Heterogeneity of the response of chronic lymphocytic leukemia cells to phorbol ester
Blood
(1982)
F. Malisan et al.
B-chronic lymphocytic leukemias can undergo isotype switching in vivo and can be induced to differentiate and switch in vitro
Blood
(1996)
M. Dono et al.
Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification
Blood
(1996)
T. Mainou-fowler et al.
Interleukin-5 (IL-5) increases spontaneous apoptosis of B-cell chronic lymphocytic leukemia cells in vitro independently of bcl-2 expression, and is inhibited by IL-4
Blood
(1994)
A.C. Fluckiger et al.
Responsiveness of chronic lymphocytic leukemia B cells activated via surface Igs or CD40 to B-cell tropic factors
Blood
(1992)
T. Ternynck et al.
Comparison of normal and CLL lymphocyte surface Ig determinants using peroxidase-labelled antibodies. I. Detection and quantitation of light chain determinants
Blood
(1974)
R.B. Slease et al.
Surface immunoglobulin density in human peripheral blood mononuclear cells
Blood
(1979)
K.A. Foon et al.
Surface markers on leukaemia and lymphoma cells
Blood
(1982)

D. Delia et al.

CD1Ic but neither CD 1a nor CD 1b molecules are expressed on normal, activated and malignant B cells. Identification of a new B cell subset

Blood

(1988)

G. Inghirami et al.

Differential expression of LFA-1 molecules in non-Hodgkin's lymphoma and lymphoid leukemias

Blood

(1988)

M. Maio et al.

Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymproliferative disorders

Blood

(1990)

S. Wormsley et al.

Characteristics of CD 1 lc+ CD5+ chronic B-cell leukemias and the identification of normal peripheral blood B-cell subsets with chronic lymphoid leukemia immunophenotypes

Blood

(1990)

R.O. Hynes

Integrins: versatility, modulation and signalling in cell adhesion

Cell

(1992)

J. Gordon et al.

Phenotypes in chronic B-lymphocytic leukemia probed by monoclonal antibodies and immunoglobulin secretion studies: identification of stages of maturation arrest and the relation to clinical findings

Blood

(1983)

D.G. Oscier

Cytogenetic and molecular abnormalities in chronic lymphocytic leukaemia

Blood Reviews

(1994)

G. Gahrton et al.

Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell stimulation

Blood

(1980)

M. Fitchett et al.

Chromosome abnormalities involving band 13814 in hematologic malignancies

Cancer Genet Cytogenet

(1987)

K. Offit et al.

6q deletions define distinct clinico-pathologic subsets of non-Hodgkin's lymphoma

Blood

(1993)

T.H. Que et al.

Trisomy 12 in chronic lymphocytic leukemia detected by fluorescence in situ hybridisation: analysis by stage, immunophenotype and morphology

Blood

(1993)

S. Stilgenbauer et al.

High frequency of monoallelic retinoblastoma gene deletion in B-cell chronic lymphoid leukemia shown by interphase cytogenetics

Blood

(1993)

Y. Liu et al.

13q deletions in lymphoid malignancies

Blood

(1995)

M.J.S. Dyer et al.

BCL2 translocations in leukemias of mature B cells

Blood

(1994)

H. Döhner et al.

p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias

Blood

(1995)

T. Watanabe et al.

The MDM2 oncogene overexpression in chronic lymphocytic leukemia and low-grade lymphoma of B-cell origin

Blood

(1994)

F. Caligaris-Cappio

B-chronic lymphocytic leukaemia: a malignancy of anti-self B cells

Blood

(1996)

E. Vandenberghe

Mantle cell lymphoma

Blood Reviews

(1994)

E. Matutes et al.

Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients

Br J Haematol

(1996)

C. Rozman et al.

Prognostic significance of bone marrow patterns in chronic lymphocytic leukaemia

Br J Haematol

(1981)

J.A. Orchard et al.

Prognostic value of Ki 67 and cell cycle analysis in chronic lymphocytic leukaemia

Br J Haematol

(1996)

A.V. Hoffbrand et al.

Autocrine and paracrine growth loops in chronic lymphocytic leukemia

Semin Haematol

(1993)

P.F. di Celle et al.

Cytokine gene expression in B-cell chronic lymphocytic leukemia: evidence of constitutive Interleukin-8 (IL-8) mRNA expression and secretion of biologically active IL-8 protein

Blood

(1994)

M. Lotz et al.

Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells

J Exp Med

(1994)

P. Panayiotidis et al.

Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro

Br J Haematol

(1996)

T.J. Hamblin et al.

Chronic lymphatic leukaemia: correlation of immunofluorescent characteristic with clinical features

Br J Haematol

(1977)

F.K. Stevenson et al.

The nature of IgG on the surface of B lymphocytes in chronic lymphocytic leukemia

J Exp Med

(1981)

S. Hashimoto et al.

Somatic diversification and selection of IgH and L chains variable region genes in IgG+, CD5+ chronic lymphocytic leukemia B cells

J Exp Med

(1995)

F. Fais et al.

Examples of in vivo isotype class switching in IgM (+) chronic lymphocytic leukemia cells

J Clin Invest

(1996)

J.P. Fermand et al.

Distribution of class 11 DC antigens on normal and leukaemic lymphoid cells

Eur J Immunol

(1985)

A.S. Freedman et al.

Expression of B cell activation antigens on normal and malignant B cells

Leukemia

(1987)

K.C. Anderson et al.

Expression of human B cell associated antigens on leukaemas and lymphomas: a model of B cell differentiation

Blood

(1984)

A.S. Freedman et al.

Immunologic markers in B-cell chronic lymphocytic leukemia

D. Catovsky et al.

Mouse red cell rosettes in B lymphoproliferative disorders

Br J Haematol

(1976)

B.J. Bain et al.

The leukaemic phase of non-Hodgkin's lymphoma

J Clin Pathol

(1995)

E. Matutes et al.

The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL

Leukemia

(1994)

F. Caligaris-Cappio et al.

B chronic lymphocytic leukemia patients with stable benign disease show a distinctive membrane phenotype

Br J Haematol

(1984)

D. Catovsky et al.

Heterogeneity of B cell leukemias demonstrated by the monoclonal antibody FMC7

Blood

(1981)

A. Orazi et al.

Distinct morphophenotypic features of chronic B lymphocytic leukemia identified with CD 1c and CD23 antibodies

Eur J Haematol

(1991)

A.S. Freedman et al.

Normal cellular counterparts of B cell chronic lymphocytic leukemia

Blood

(1987)

Cited by (60)

The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia
2012, Blood
Citation Excerpt :
Our analysis, in line with other reports, describe deregulated expression levels for various components of the BCR signaling complex in CLL B cells compared with normal B cells. In regard to this point, it has been established that low levels of BCR is a hallmark of CLL B cells because of an incorrect folding of both IgM and CD79a.3,8,15,16 However, based on the differential in vitro survival readout, B cells from the responder group express higher surface IgM levels compared with nonresponding cells.
B-cell antigen receptor (BCR)–mediated signaling plays a critical role in chronic lymphocytic leukemia (CLL) pathogenesis and gives an in vitro survival advantage to B cells isolated from patients with unfavorable prognostic factors. In this study, we undertook to elucidate the signaling intermediates responsible for this biologic alteration. In responding cells only, in vitro BCR engagement triggers global phosphorylation of Syk, activation of phospholipase Cγ2, and intracellular calcium mobilization, reflecting competency of BCR signaling. The calcium–calcineurin-dependent transcription factor NFAT2 is up-regulated and to some extent constitutively activated in all CLL B cells. In contrast, its DNA-binding capacity is enhanced on IgM stimulation in responding cells only. NFAT inhibition using the VIVIT peptide prevents induction of CD23 target gene and IgM-induced survival, converting responding cells to unresponsive status. At the opposite, ionomycin-induced NFAT activity allows survival of nonresponding cells. These results demonstrate that the functional heterogeneity relies on variability of protein levels establishing BCR-dependent thresholds and NFAT-dependent activation. Finally, status of the BCR-NFAT pathway for each patient reveals its relevance for CLL clinical outcome and points out to BCR-NFAT intermediates as promising functional therapeutic targets.
Dual inhibition of the homologous recombinational repair and the nonhomologous end-joining repair pathways in chronic lymphocytic leukemia therapy
2011, Leukemia Research
Citation Excerpt :
B-cell chronic lymphocytic leukemia (CLL) is a complex disease characterized by actively dividing B-lymphocyte in the lymph nodes and bone marrow [1,2] as well as the accumulation of quiescent lymphocytes in the peripheral blood of affected patients [3].
Resistance to chlorambucil in chronic lymphocytic leukemia (CLL) has been associated with increased DNA repair. Specifically, inhibition of either c-abl, which modulates Rad51 directed homologous recombination or DNA-PK dependent nonhomologous end joining has been shown to sensitize primary CLL lymphocytes to chlorambucil. Here we report that inhibition of c-abl can result in a compensatory increase in DNA-PK and thus inhibition of both c-abl and DNA-PK optimally sensitizes CLL lymphocytes to chlorambucil. In this paper we report a drug-induced compensatory change between two DNA repair pathways with potential therapeutic implications in CLL therapy.
Dipeptidyl peptidase 2 apoptosis assay determines the B-cell activation stage and predicts prognosis in chronic lymphocytic leukemia
2010, Experimental Hematology
Citation Excerpt :
However, concomitant exposure of R-CLL to AX8819 and 17-AAG−enhanced apoptosis, resulting in death of 17.8% ± 3.0% CD19+ CLL B cells over background (range, 0−23%; Fig. 6B). The prevailing view is that CLL is an accumulative disease with B cells arrested in G0 [32,33]. However, heterogeneity of clinical outcome in CLL points to the complexity of the disease biology.
Dipeptidyl peptidase 2 (DPP2/DPP7) is a regulator of quiescence as inhibition of DPP2 results in apoptosis of resting, but not activated lymphocytes. The purpose of the present study was to investigate the prognostic value of DPP2 inhibition and the role of DPP2 in cell cycle in chronic lymphocytic leukemia (CLL).
We screened 152 peripheral blood samples from patients with CLL in an apoptosis assay with AX8819, a DPP2-specific inhibitor. The apoptotic response was correlated with B-cell receptor signaling and cell cycle and molecular prognostic factors.
We categorized CLL into two prognostic subgroups. Inhibition of DPP2 induced apoptosis in 60% of CLL, while 40% were resistant to apoptosis. Resistance to apoptosis correlated with unmutated IgV_H and increased ZAP-70 expression and was associated with unfavorable clinical outcomes. Sensitive CLL B cells expressed high p27, low c-Myc protein levels and decreased Syk phosphorylation, indicative of a resting phenotype. DPP2 inhibition in those cells resulted in apoptosis accompanied by enhanced phosphorylation of Syk, degradation of p27 and p130, and upregulation of c-Myc, indicative of activation and inappropriate cell cycle entry. Resistant CLL demonstrated baseline low p27 and high c-Myc protein levels and increased pSyk, indicative of an activated phenotype. Inhibition of heat shock protein 90 in this subset of CLL partially reversed apoptosis resistance.
The DPP2 apoptosis assay provides a reliable prognostic factor in CLL. CLL B cells sensitive to DPP2 inhibition are in true G₀, while resistant CLL B-cells are partially activated. DPP2 inhibition alone or with concomitant inhibition of heat shock protein 90 warrants investigation as a therapeutic modality in CLL.
Immuno-regulatory malignant B cells contribute to Chronic Lymphocytic Leukemia progression
2023, Cancer Gene Therapy
Analysis of immunoglobulin heavy variable chain rearrangement in chronic lymphocytic leukemia patients among chornobyl clean-up workers
2020, Experimental Oncology
Assessment of micro RNAs expression in leukemic cells as prognostic markers in chronic lymphocytic leukemia: Micro RNAs can predict survival in a course of the disease
2018, Oncotarget

View all citing articles on Scopus

View full text