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

Chronic lymphocytic leukemia is a disease with long natural evolution, receiving low efficiency therapy and rarely with complete response to treatment. More and more patients are diagnosed in asymptomatic stages and at younger ages. Recent progress in uncovering the molecular mechanisms involved in the pathogenesis of the disease, accompanied by the emergence of new therapeutic agents, generates an ongoing challenge for clinicians in establishing optimal therapeutic management of these patients. In parallel, studies were conducted to highlight the factors that effectively influence therapeutic response and duration of response – prognostic markers – in order to adopt the best therapeutic strategy for the patient. Although clinical staging remains the basis for evaluating prognosis in chronic lymphocytic leukemia, a number of biological markers, in particular serum markers, cytogenetic abnormalities, IgVH mutation status, CD38 and ZAP-70 expression in leukemic cells, provides important and independent prognostic information. Before being incorporated into everyday clinical practice, however, these markers require, standardization and validation in larger prospective studies. Currently they try to combine these prognostic markers in order to obtain an integrated risk stratification system, with broad clinical application.

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Association of Bax Expression and Bcl2/Bax Ratio with Clinical and Molecular Prognostic Markers in Chronic Lymphocytic Leukemia

Journal of Medical Biochemistry ◽

10.1515/jomb-2015-0017 ◽

2016 ◽

Vol 35 (2) ◽

pp. 150-157 ◽

Cited By ~ 11

Author(s):

Ksenija Vucicevic ◽

Vladimir Jakovljevic ◽

Natasa Colovic ◽

Natasa Tosic ◽

Tatjana Kostic ◽

...

Keyword(s):

Gene Expression ◽

Chronic Lymphocytic Leukemia ◽

Mononuclear Cells ◽

Prognostic Markers ◽

Statistical Significance ◽

Genetic Alterations ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Aberrant Expression ◽

Mutational Status

Summary Background: In chronic lymphocytic leukemia (CLL), in vivo apoptotic resistance of malignant B lymphocytes results, in part, from the intrinsic defects of their apoptotic machinery. These include genetic alterations and aberrant expression of many apoptosis regulators, among which the Bcl2 family members play a central role. Aim: The aim of this study was to investigate the association of pro-apoptotic Bax gene expression and Bcl2/Bax ratio with the clinical features of CLL patients as well as with molecular prognostic markers, namely the mutational status of rearranged immunoglobulin heavy variable (IGHV) genes and lipoprotein lipase (LPL) gene expression. Methods: We analyzed the expression of Bax mRNA and Bcl2/Bax mRNA ratio in the peripheral blood mononuclear cells of 58 unselected CLL patients and 10 healthy controls by the quantitative reverse-transcriptase polymerase chain reaction. Results: We detected significant Bax gene overexpression in CLL samples compared to non-leukemic samples (p=0.003), as well as an elevated Bcl2/Bax ratio (p=<0.001). Regarding the association with prognostic markers, the Bcl2/Bax ratio showed a negative correlation to lymphocyte doubling time (r=−0.307; p=0.0451), while high-level Bax expression was associated with LPL-positive status (p=0.035). Both the expression of Bax and Bcl2/Bax ratio were higher in patients with unmutated vs. mutated IGHV rearrangements, but this difference did not reach statistical significance. Conclusions: Our results suggest that dysregulated expression of Bcl2 and Bax, which leads to a high Bcl2/Bax ratio in leukemic cells, contributes to the pathogenesis and clinical course of CLL.

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Implications of new prognostic markers in chronic lymphocytic leukemia

Hematology ◽

10.1182/asheducation.v2012.1.76.3806845 ◽

2012 ◽

Vol 2012 (1) ◽

pp. 76-87 ◽

Cited By ~ 38

Author(s):

Nicholas Chiorazzi

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Kinase Inhibitors ◽

Prognostic Markers ◽

Specific Property ◽

Molecular Techniques ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Prognostic Indicators ◽

Molecular Characteristics ◽

Specific Proteins

Abstract Several prognostic markers based on genetic, phenotypic, and molecular characteristics of chronic lymphocytic leukemia (CLL) B cells have emerged in the past decade. The clinical utility of these newer prognostic indicators, alone or in combination with each other and other clinical predictive systems, is still being determined. This chapter attempts to define biologic and molecular underpinnings of 3 sets of prognostic indicators in CLL: genetic abnormalities quantified by FISH and/or defined by exploratory sensitive molecular techniques, expression of specific proteins in or on CLL cells (ie, CD38, CD49d, and ZAP-70), and the IGHV mutation status of a CLL clone. Although not demonstrated conclusively, each probably reflects the biologic properties of the leukemic cells of individual CLL patients. This reflection may be direct, indicating a specific property of the CLL cell itself, or indirect, representing how the CLL cell interacts with the host's microenvironment. The new tyrosine kinase inhibitors that are currently in clinical trials support this interpretation. These and other biology-based indicators of patient clinical course and outcome can be used as starting points from which to understand and treat CLL.

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The pathological features of leukemic cells infiltrating the renal interstitium in chronic lymphocytic leukemia/small lymphocytic lymphoma from a large single Chinese center

Diagnostic Pathology ◽

10.1186/s13000-021-01120-4 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Hui Wang ◽

Xiaojuan Yu ◽

Xu Zhang ◽

Suxia Wang ◽

Minghui Zhao

Keyword(s):

Electron Microscopy ◽

Chronic Lymphocytic Leukemia ◽

Renal Injury ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Cell Infiltration ◽

Small Lymphocytic Lymphoma ◽

Tubulointerstitial Injury ◽

Renal Interstitium ◽

Monoclonal Immunoglobulins

Abstract Background Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare in Asians, and patients with CLL/SLL seldomly undergo kidney biopsy. The histopathological features and clinical relevance of tubulointerstitial injury in CLL/SLL have not been extensively characterized. Hence, we attempted to describe the clinical characteristics, renal pathology and clinical outcome of a well-characterized population of CLL/SLL patients with CLL cell infiltration in the renal interstitium from a large single center in China. Methods Between January 1st, 2010 and September 31st, 2020, 31946renal biopsies were performed at Peking University First Hospital, and 10 CLL/SLL patients with CLL cell infiltration in the renal interstitium were included. Complete clinical data were collected from these 10 patients, and renal specimens were examined by routine light microscopy, immunofluorescence and electron microscopy. Results The extent of the infiltrating CLL cells in patients with CLL/SLL varied among different patients and ranged from 10 to 90% of kidney parenchyma. Six (60%) of 10 patients presented with an extent of infiltrating CLL cells ≥50%. Interestingly, we found that three patients (3/10, 30%) expressed monoclonal immunoglobulins in the infiltrating CLL cells, and special cytoplasmic crystalline structures were found in two of the three patients by electron microscopy for the first time. Severe renal insufficiency (Scr ≥200 μmol/L) was associated with ≥50% interstitial infiltration of CLL cells in the renal interstitium. Conclusions The current study confirmed that CLL cells infiltrating the renal interstitium can directly secrete monoclonal immunoglobulins, indicating that the interstitial infiltrating CLL cells possibly cause renal injury directly by secreting monoclonal immunoglobulins in situ. This finding may prove a new clue to elucidate the pathogenetic mechanism of renal injury involved with CLL/SLL.

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In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2006-01-013003 ◽

2006 ◽

Vol 108 (4) ◽

pp. 1135-1144 ◽

Cited By ~ 96

Author(s):

Silvia Deaglio ◽

Tiziana Vaisitti ◽

Semra Aydin ◽

Enza Ferrero ◽

Fabio Malavasi

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Prognostic Markers ◽

Diagnostic Marker ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Affinity Ligand ◽

Survival Potential ◽

Receptor Cross Talk ◽

Indirect Confirmation ◽

High Affinity Ligand

Abstract The absence of mutations in the IgV genes, together with the presence of ZAP-70 and CD38, are the most reliable negative prognostic markers for chronic lymphocytic leukemia (CLL) patients. Several lines of evidence indicate that CD38 may be not only a diagnostic marker but also a key element in the pathogenetic network in CLL. First, CD38 is a receptor that induces proliferation and increases survival of CLL cells. Second, CD38 signals start upon interaction with the CD31 ligand expressed by stromal and nurse-like cells. Third, CD38/CD31 contacts up-regulate CD100, a semaphorin involved in sustaining CLL growth. Fourth, evidence that nurselike cells express high levels of CD31 and plexin-B1, the high-affinity ligand for CD100, offers indirect confirmation for this model of receptor cross-talk. Elements of variation in the clinical course of CD38+ CLL patients include (1) potential intersection with ZAP-70, a kinase involved in the CD38 signaling pathway in T and natural killer (NK) cells, and (2) the effects of genetic polymorphisms of the receptors involved, at least of CD38 and CD31. Consequently, CD38 together with ZAP-70 appear to be the key elements of a coreceptor pathway that may sustain the signals mediated by the B-cell receptor and potentially by chemokines and their receptors. This would result in acquisition of increased survival potential, providing clues to the poorer prognosis of CD38+ patients.

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Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v65.2.340.340 ◽

1985 ◽

Vol 65 (2) ◽

pp. 340-344 ◽

Cited By ~ 33

Author(s):

L Baldini ◽

R Mozzana ◽

A Cortelezzi ◽

A Neri ◽

F Radaelli ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Clinical Stage ◽

Prognostic Significance ◽

Prognostic Index ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Clinical Prognosis ◽

Delta Type ◽

Cell Chronic Lymphocytic Leukemia

Abstract Seventy-six consecutive untreated patients with B cell chronic lymphocytic leukemia (B-CLL) and classified according to Binet's staging system were studied at the clinical presentation. Several immunologic parameters (number of total and T circulating lymphocytes and their surface membrane immunoglobulin [Smlg] phenotypes and levels of serum Ig) were evaluated with the aim of identifying a biologic marker of prognostic relevance. In this series of persons, Binet staging confirmed its usefulness as a prognostic index (P less than .001). With regard to Smlg, they were mu-type in 41 cases (53.9%), mu- type plus delta-type in 29 cases (38.2%), alpha-type in one case, and not detectable in five cases. No correlations were found between clinical stage and immunoglobulin phenotype, although all but one patient in stage C showed mu-type Smlg alone. On analyzing the survival curves of our patients according to different Smlg phenotypes, we found that patients with only mu-type Smlg had a poorer prognosis (P less than .05) than those with mu-type plus delta-type; this difference was even more significant (P less than .01) in patients in stage A, whereas there were no statistical differences in those in stages B and C. Because the appearance of surface heavy chain of delta-type could be an expression of cell maturation, these results suggest that in B-CLL the presence of phenotypically more mature leukemic cells may correlate with better clinical prognosis, particularly in the early phase of the disease.

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Assessment of microRNA expression in leukemic cells as predictors of sensitivity to purine nucleoside analogs, fludarabine and cladribine, in chronic lymphocytic leukemia patients

Cancer Management and Research ◽

10.2147/cmar.s191311 ◽

2019 ◽

Vol Volume 11 ◽

pp. 5021-5031

Author(s):

Agnieszka Szymczyk ◽

Sylwia Chocholska ◽

Arkadiusz Macheta ◽

Dariusz Szczepanek ◽

Marek Hus ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Nucleoside Analogs ◽

Microrna Expression ◽

Lymphocytic Leukemia ◽

Purine Nucleoside ◽

Leukemic Cells

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Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival

Blood ◽

10.1182/blood-2002-02-0558 ◽

2002 ◽

Vol 100 (8) ◽

pp. 2973-2979 ◽

Cited By ~ 164

Author(s):

Anne J. Novak ◽

Richard J. Bram ◽

Neil E. Kay ◽

Diane F. Jelinek

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

B Lymphocyte ◽

Leukemic Cell ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Aberrant Expression ◽

B Lymphocyte Stimulator

B-cell chronic lymphocytic leukemia (B-CLL) is defined by the accumulation of CD5+ B cells in the periphery and bone marrow. This disease is not characterized by highly proliferative cells but rather by the presence of leukemic cells with significant resistance to apoptosis and, therefore, prolonged survival. B-lymphocyte stimulator (BLyS) is a newly identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis and it shares significant homology with another TNF superfamily member, APRIL. The striking effects of BLyS on normal B-cell maintenance and survival raises the possibility that it may be involved in pathogenesis and maintenance of hematologic malignancies, including B-CLL. In this study, we investigated the status of APRIL and BLyS expression, as well as their receptors, in this disease. All B-CLL patient cells studied expressed one or more of 3 known receptors for BLyS; however, the pattern of expression was variable. In addition, we demonstrate for the first time that B-CLL cells from a subset of patients aberrantly express BLyS and APRIL mRNA, whereas these molecules were not detectable in normal B cells. Furthermore, we provide in vitro evidence that BLyS protects B-CLL cells from apoptosis and enhances cell survival. Because these molecules are key regulators of B-cell homeostasis and tumor progression, leukemic cell autocrine expression of BLyS and APRIL may be playing an important role in the pathogenesis of this disease.

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Battle of Thermopylae: 300 Spartans (natural killer cells plus obinutuzumab) versus the immortal warriors (chronic lymphocytic leukemia cells) of Xerxes’ army

Future Science OA ◽

10.2144/fsoa-2019-0064 ◽

2019 ◽

Vol 5 (10) ◽

pp. FSO425

Author(s):

Ricardo García-Muñoz ◽

María-Josefa Nájera ◽

Jesús Feliu ◽

Judith Antón-Remírez ◽

Enrique Ramalle-Gómara ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Nk Cells ◽

Natural Killer ◽

Peripheral Blood ◽

Nk Cell ◽

Killer Cell ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Lymphokine Activated Killer Cells ◽

Killer Cells

Aim: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. Patients & methods: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. Results: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. Conclusion: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells.

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Heterogeneity of the response of chronic lymphocytic leukemia cells to phorbol ester

Blood ◽

10.1182/blood.v60.5.1082.1082 ◽

1982 ◽

Vol 60 (5) ◽

pp. 1082-1088 ◽

Cited By ~ 20

Author(s):

J Okamura ◽

EW Gelfand ◽

M Letarte

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Phorbol Ester ◽

Mixed Lymphocyte Reaction ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Leukemia Cells ◽

Phenotypic Markers ◽

Tumor Promotor ◽

Bright Surface

Abstract The ability of the tumor promotor 12–0-tetradecanoylphorbol 13-acetate (TPA) to induce differentiation of leukemic cells was studied in 10 cases of chronic lymphocytic leukemia (CLL). An increase in modal volume and an enhancement of the capacity of te leukemic cells to stimulate in mixed lymphocyte reaction (MLR) was seen in the majority of cases. A significant increase in Ia expression was observed upon culture of leukemic cells with TPA in 6 of the 10 cases; 5 of these cases also showed an induction of cytoplasmic IgM production. Correlations between the phenotypic markers of the leukemic cells and their ability to respond to TPA were evaluated. CLL cells with low amounts to surface Ig. a volume less than or equal to 165 fl. and relatively low la expression responded well to TPA. Cells with bright surface Ig. a volume greater than or equal to 178 fl. and elevated amounts of Ia responded poorly to TPA. These results suggest that differences in the response of B leukemic cells to TPA reflect the underlying heterogeneity of the leukemic cells and might be correlated with their stage of maturation.

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