Multi-drug resistance in B-cell chronic lymphocytic leukemia (B-CLL): A feature of B-CLL sub-sets with poor prognosis genetic alterations?

The most frequent chromosomal aberrations in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q, 11q, and 17p, and trisomy 12, all of which are of prognostic significance. Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) are used for their detection, but cytogenetic analysis is hampered by the low mitotic index of B-CLL cells, and FISH depends on accurate information about candidate regions. We used a set of 400 highly informative microsatellite markers covering all chromosomal arms (allelotyping) and automated polymerase chain reaction (PCR) protocols to screen 46 patients with typical B-CLL for chromosomal aberrations. For validation, we compared data with our conventional karyotype results and fine mapping with conventional single-site PCR. All clonal cytogenetic abnormalities potentially detectable by our microsatellite PCR (eg, del13q14 and trisomy 12) were picked up. Allelotyping revealed additional complex aberrations in patients with both normal and abnormal B-CLL karyotypes. Aberrations detectable in the samples with our microsatellite panel were found on almost all chromosomal arms. We detected new aberrant loci in typical B-CLL, such as allelic losses on 1q, 9q, and 22q in up to 25% of our patients, and allelic imbalances mirroring chromosomal duplications, amplifications, or aneuploidies on 2q, 10p, and 22q in up to 27% of our patients. We conclude that allelotyping with our battery of informative microsatellites is suitable for molecular screening of B-CLL. The technique is well suited for analyses in clinical trials, it provides a comprehensive view of genetic alterations, and it may identify new loci with candidate genes relevant in the molecular biology of B-CLL.

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Susceptibility Alleles for Aberrant B-1 Cell Proliferation Involved in Spontaneously Occurring B-Cell Chronic Lymphocytic Leukemia in a Model of New Zealand White Mice

Blood ◽

10.1182/blood.v92.10.3772.422k10_3772_3779 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3772-3779

Author(s):

Yoshitomo Hamano ◽

Sachiko Hirose ◽

Akinori Ida ◽

Masaaki Abe ◽

Danqing Zhang ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Autoimmune Disease ◽

B Cell ◽

Genetic Alterations ◽

Lymphocytic Leukemia ◽

Chromosome 17 ◽

Mouse Strains ◽

Autoantibody Production ◽

Age Related ◽

Cell Chronic Lymphocytic Leukemia

B-cell chronic lymphocytic leukemia (B-CLL) and autoimmune disease are a related event, and genetic factors are linked to both diseases. As B-CLL is mainly of B-1 cell type that participates in autoantibody production, genetically-determined regulatory abnormalities in proliferation and/or differentiation of B-1 cells may determine their fate. We earlier found that, in H-2–congenic (NZB × NZW) F1 mice, while H-2d/z heterozygosity predisposes to autoimmune disease, H-2z/z homozygosity predisposes to B-CLL. Studies also suggested the involvement of non–H-2-linked NZW allele(s) in leukemogenesis. Using H-2–congenic NZW and B10 mouse strains, their F1 and backcross progeny, we have now identified three major NZW susceptibility loci for abnormal proliferation of B-1 cells, which form the basis of leukemogenesis; one H-2–linked locus on chromosome 17 and the other two non–H-2-linked loci, each on chromosome 13 and chromosome 17. Each susceptibility allele functioned independently, in an incomplete dominant fashion, the sum of effects determining the extent of aberrant B-1 cell frequencies. The development of leukemia was associated with age-related increase in B-1 cell frequencies in the blood. Thus, these alleles probably predispose B-1 cells to accumulate genetic alterations, giving rise to B-CLL. Potentially important candidate genes and correlation of the findings with autoimmune disease are discussed.

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Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells

Frontiers in Immunology ◽

10.3389/fimmu.2016.00454 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 12

Author(s):

Diego Sánchez-Martínez ◽

Pilar M. Lanuza ◽

Natalia Gómez ◽

Aura Muntasell ◽

Elisa Cisneros ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Nk Cells ◽

Poor Prognosis ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Cell Chronic Lymphocytic Leukemia

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Increased expression of angiopoietin-2 characterizes early B-cell chronic lymphocytic leukemia with poor prognosis

Leukemia Research ◽

10.1016/j.leukres.2007.09.002 ◽

2008 ◽

Vol 32 (4) ◽

pp. 593-597 ◽

Cited By ~ 13

Author(s):

Silvia Martinelli ◽

Rossana Maffei ◽

Ilaria Castelli ◽

Rita Santachiara ◽

Patrizia Zucchini ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Poor Prognosis ◽

Lymphocytic Leukemia ◽

Angiopoietin 2 ◽

Cell Chronic Lymphocytic Leukemia

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Relationship between nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia (B-CLL) and protein expression of Bcl-2, Bax, Bcl-X and p53

Cancer Letters ◽

10.1016/s0304-3835(97)00336-4 ◽

1997 ◽

Vol 121 (1) ◽

pp. 59-67 ◽

Cited By ~ 12

Author(s):

G Christodoulopoulos ◽

N Fotouhi ◽

S Krajewski ◽

J.C Reed ◽

M Alaoui-Jamali ◽

...

Keyword(s):

Drug Resistance ◽

Chronic Lymphocytic Leukemia ◽

Protein Expression ◽

B Cell ◽

Nitrogen Mustard ◽

Lymphocytic Leukemia ◽

Cell Chronic Lymphocytic Leukemia

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p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression

Blood ◽

10.1182/blood.v82.11.3452.bloodjournal82113452 ◽

1993 ◽

Vol 82 (11) ◽

pp. 3452-3459 ◽

Cited By ~ 4

Author(s):

S el Rouby ◽

A Thomas ◽

D Costin ◽

CR Rosenberg ◽

M Potmesil ◽

...

Keyword(s):

Drug Resistance ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Gene Mutations ◽

P53 Gene ◽

Lymphocytic Leukemia ◽

P53 Mutations ◽

P53 Gene Mutation ◽

P53 Gene Mutations ◽

Cell Chronic Lymphocytic Leukemia

We studied 53 patients with B-cell chronic lymphocytic leukemia (B-CLL) and found mutations of the p53 gene in 15%. Patients with p53 gene mutations were found to have an aggressive form of B-CLL disease characterized by advanced Rai stage, rapid lymphocyte doubling time (LDT), and resistance to chemotherapy. While 27 of 29 treated patients (93%) without p53 mutations achieved a partial remission, only one of seven treated patients (14%) with p53 mutations achieved a partial remission (P = .00009). Adjusting for prognostic factors (age, sex, race, and Rai stage), patients with p53 gene mutations had a 13-fold greater risk of death than patients without p53 mutations (P = .013). In addition to examining the clinical relevance of p53 gene mutations in B-CLL, we investigated the possible role of p53 gene regulation in the expression of the multidrug resistance genes MDR1 and MDR3. We quantitated MDR1 and MDR3 mRNA expression by reverse transcription- polymerase chain reaction (RT-PCR). Expression of both the MDR1 and MDR3 genes was independent of p53 gene mutation or prior drug treatment, and did not predict for clinical response. Our findings indicate that p53 gene mutations in B-CLL are associated with a poor clinical outcome and may be a prognostic indicator for drug resistance.

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Drug resistance in B-cell chronic lymphocytic leukemia: Predictable by in vitro evaluation with a multiparameter flow cytometric cytotoxicity assay

Cytometry Part B Clinical Cytometry ◽

10.1002/cyto.b.20117 ◽

2007 ◽

Vol 72B (3) ◽

pp. 189-195 ◽

Cited By ~ 7

Author(s):

Yanping Zhong ◽

Antony C. Bakke ◽

Guang Fan ◽

Rita M. Braziel ◽

Ken M. Gatter ◽

...

Keyword(s):

Drug Resistance ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cytotoxicity Assay ◽

Lymphocytic Leukemia ◽

In Vitro Evaluation ◽

Flow Cytometric ◽

Cell Chronic Lymphocytic Leukemia

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Susceptibility Alleles for Aberrant B-1 Cell Proliferation Involved in Spontaneously Occurring B-Cell Chronic Lymphocytic Leukemia in a Model of New Zealand White Mice

Blood ◽

10.1182/blood.v92.10.3772 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3772-3779 ◽

Cited By ~ 27

Author(s):

Yoshitomo Hamano ◽

Sachiko Hirose ◽

Akinori Ida ◽

Masaaki Abe ◽

Danqing Zhang ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Autoimmune Disease ◽

B Cell ◽

Genetic Alterations ◽

Lymphocytic Leukemia ◽

Chromosome 17 ◽

Mouse Strains ◽

Autoantibody Production ◽

Age Related ◽

Cell Chronic Lymphocytic Leukemia

Abstract B-cell chronic lymphocytic leukemia (B-CLL) and autoimmune disease are a related event, and genetic factors are linked to both diseases. As B-CLL is mainly of B-1 cell type that participates in autoantibody production, genetically-determined regulatory abnormalities in proliferation and/or differentiation of B-1 cells may determine their fate. We earlier found that, in H-2–congenic (NZB × NZW) F1 mice, while H-2d/z heterozygosity predisposes to autoimmune disease, H-2z/z homozygosity predisposes to B-CLL. Studies also suggested the involvement of non–H-2-linked NZW allele(s) in leukemogenesis. Using H-2–congenic NZW and B10 mouse strains, their F1 and backcross progeny, we have now identified three major NZW susceptibility loci for abnormal proliferation of B-1 cells, which form the basis of leukemogenesis; one H-2–linked locus on chromosome 17 and the other two non–H-2-linked loci, each on chromosome 13 and chromosome 17. Each susceptibility allele functioned independently, in an incomplete dominant fashion, the sum of effects determining the extent of aberrant B-1 cell frequencies. The development of leukemia was associated with age-related increase in B-1 cell frequencies in the blood. Thus, these alleles probably predispose B-1 cells to accumulate genetic alterations, giving rise to B-CLL. Potentially important candidate genes and correlation of the findings with autoimmune disease are discussed.

Download Full-text