Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features

Guarini, Anna; Gaïdano, Gianluca; Mauro, Francesca Romana; Capello, Daniela; Mancini, Francesca; Propris, Maria Stefania De; Mancini, Marco; Orsini, Enrica; Gentile, Massimo; Breccia, Massimo; Cuneo, Antonio; Castoldi, Gianluigi; Foà, Robert

doi:10.1182/blood-2002-12-3639

Cited by 76 publications

(66 citation statements)

References 36 publications

(28 reference statements)

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“…The median level of CD38 among ZAP-70-negative cases was 5.3%, when compared with 27.2% among ZAP-70-positive cases (P < 0.0001) (36). This is consistent with other investigators who have used CD38 and ZAP-70 expression to predict the time to first treatment (8,9,11,18,33,39 A and B).…”

Section: Considerations For the Combined Measurement Of Cd38 And Zap-70supporting

confidence: 88%

“…The expression of CD38 expression has been shown to be unstable over time in some patients and not in others (8)(9)(10)12,14,(29)(30)(31)(32)(33)(34) and there has been disagreement about which cutoff value to use for CD38 positivity for defining prognosis. Some investigators have used 7% (14,15,18,28), others 20% (10,13), and still others 30% (8,9,11,12,31).…”

Section: Considerations For the Measurement Of Cd38mentioning

confidence: 99%

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Clinical utility of assessing ZAP‐70 and CD38 in chronic lymphocytic leukemia

Rassenti

Kipps

2006

Cytometry Part B Clinical

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Section: Considerations For the Combined Measurement Of Cd38 And Zap-70supporting

confidence: 88%

Section: Considerations For the Measurement Of Cd38mentioning

confidence: 99%

Clinical utility of assessing ZAP‐70 and CD38 in chronic lymphocytic leukemia

Rassenti

Kipps

2006

Cytometry Part B Clinical

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“…17 These 25 cases represented the B-CLL patients matching the criteria for highly stable B-CLL and consecutively seen at the outpatient clinic during a 3-month period.…”

Section: Patients and Database Constructionmentioning

confidence: 99%

“…[4][5][6]16 Recently, we reported on a series of highly stable and indolent B-CLL patients who never required treatment over prolonged follow-up. 17 Here, we address the issue of a potential V H and V L bias in these highly stable B-CLL. We report that a significant subset of highly stable B-CLL patients in our series utilize the V H gene V H 3-72 and, in some cases, express V H and V L sequences with homologous CDR3s, suggesting recognition of a common antigen.…”

Section: Introductionmentioning

confidence: 99%

Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia

et al. 2004

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Recognition of biased immunoglobulin variable (IgV) gene usage in B-cell chronic lymphocytic leukemia (B-CLL) may yield insight into leukemogenesis and may help to refine prognostic categories. We explored Ig variable heavy (V H ) and light (V L ) chain gene usage in highly stable and indolent B-CLL (n ¼ 25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated V H 3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; Po0.01), including mutated cases (6/432; 1.39%; Po0.01) and was exceptional among indolent (1/230, 0.435%; Po0.01), and aggressive B-cell lymphomas (0/105; Po0.01). Three of six V H 3-72 B-CLL cases utilized the same V L V j 4-1 gene. Two V H 3-72 B-CLL cases had highly homologous V H complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized V j 4-1 genes with homologous IgV L CDR3s. An identical threonine to isoleucine change at codon 84 of V H 3-72 framework region 3 (FR3) recurred in four cases of highly stable V H 3-72 B-CLL. This mutation is expected to cause a conformational change of FR3 proximal to CDR3 that might critically affect high-affinity antigen binding. B-cell receptors encoded by V H 3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.

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“…Subsequently, novel prognostic factors have been defined: lymphocyte doubling time (LDT), pattern of bone marrow infiltration, LDH, serum b2-microglobulin, soluble CD23, serum thymidine kinase, expression of CD38, cytogenetic aberrations and mutational status of immunoglobulin heavy chain variable region genes (IGV H ). [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Of these, cytogenetics and IGV H mutational status are currently the best predictors of outcome, independent of clinical stage. [13][14][15] However, their use is restricted to specialized laboratories and therefore a small number of patients.…”

Section: Introductionmentioning

confidence: 99%

High expression of activation-induced cytidine deaminase (AID) mRNA is associated with unmutated IGVH gene status and unfavourable cytogenetic aberrations in patients with chronic lymphocytic leukaemia

et al. 2004

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Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation of B-cells. We investigated the expression of AID mRNA by real-time polymerase chain reaction (PCR) in peripheral blood mononuclear cells of 80 patients with B-CLL. AID expression was detected in 45 of 80 patients (56%) at various levels, but was undetectable in 35 patients (44%). AID PCR positivity was associated with unmutated IGV H gene status (22 of 25 patients; P ¼ 0.002) and unfavourable cytogenetics (18 of 23 patients with deletion in 11q or loss of p53; P ¼ 0.040). Using a threshold level of 0.01-fold expression compared to Ramos control cells, even more significant associations were observed (P ¼ 0.001 for IGV H ; P ¼ 0.002 for cytogenetics). A correlation was observed between individual AID levels and the percentage of V H homology (R ¼ 0.41; P ¼ 0.001). AID positivity predicted unmutated IGV H status with an odds ratio of 8.31 (P ¼ 0.003) and poor risk cytogenetics with an odds ratio of 3.46 (P ¼ 0.032). Significance was retained after adjustment for Binet or Rai stages. AID mRNA levels were stable over time. These data suggest a potential role of AID as a prognostic marker in B-CLL.

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Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features

Cited by 76 publications

References 36 publications

Clinical utility of assessing ZAP‐70 and CD38 in chronic lymphocytic leukemia

Clinical utility of assessing ZAP‐70 and CD38 in chronic lymphocytic leukemia

Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia

High expression of activation-induced cytidine deaminase (AID) mRNA is associated with unmutated IGVH gene status and unfavourable cytogenetic aberrations in patients with chronic lymphocytic leukaemia

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