Mutational status of IgVH genes in B-cell chronic lymphocytic leukemia and prognosis: percent mutations or antigen-driven selection?

Bomben, Riccardo; Bo, Michele Dal; Zucchetto, Antonella; Zaina, Eva; Nanni, Paola; Sonego, Paolo; Poeta, Giovanni Del; Degan, Massimo; Gattei, Valter

doi:10.1038/sj.leu.2403830

Cited by 21 publications

(27 citation statements)

References 8 publications

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“…The optimal cut off for CD69 expression yielding the best separation of CLL patients into 2 subsets with significantly different prognosis was fixed at 30% of positive cells by applying the most commonly used methods. 9,13,32,34 Since our proposal is to use CD69 for prognostic purposes, we confirmed its inter-laboratory reproducibility and the stability over time of its expression. 21,35 We demonstrated that CD69 expression was significantly correlated with CD38, CD49d and ZAP-70 and IGHV mutational status.…”

Section: Discussionsupporting

confidence: 51%

“…The resulting cDNAs, checked for first strand synthesis, 32 were amplified using a mixture of sense primers annealing to either VH1 through VH6 leader sequences or 5' ends of VH1-VH6 FR1. Purified amplicons were cloned and a minimum of 10-20 colonies for each case were sequenced; CLL specific IGHV transcripts, identified by sharing the same CDR3 in multiple clones were analyzed for percent mutation, as previously described.…”

Section: Ighv Mutation Analysismentioning

confidence: 99%

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CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study

Poeta

Principe²,

Zucchetto³

et al. 2011

Haematologica

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BackgroundCD69 is expressed in several hemopoietic cells and is an early activation marker in chronic lymphocytic leukemia. Chronic lymphocytic leukemia is a clinically heterogeneous disease which needs novel prognostic parameters which can be easily and efficiently managed. Design and MethodsWe investigated CD69 by flow cytometry in a series of 417 patients affected by chronic lymphocytic leukemia and compared this to other biological and clinical prognosticators. ResultsCD69 was associated with Rai stages (P=0.00002), b2-microglobulin (P=0.0005) and soluble CD23 (P<0.0001). CD69 and ZAP-70 (P=0.018) or CD38 (P=0.00015) or immunoglobulin variable heavy chain gene mutations (P=0.0005) were also significantly correlated. Clinically, CD69 positive chronic lymphocytic leukemias received chemotherapy more frequently (74%; P<0.0001), and presented a shorter duration of response after fludarabine plus rituximab (P=0.010) as well as shorter progression free survival and overall survival (P<0.0001). CD69 demonstrated true additive prognostic properties, since the CD69 + plus ZAP-70 + or CD38 + or immunoglobulin variable heavy chain gene unmutated patients had the worst progression free survival and overall survival (P<0.0001). Interestingly, low CD69 expression was necessary to correctly prognosticate the longer progression free survival of patients with a low tumor burden of b2-microglobulin (P=0.002), of soluble CD23 (P=0.020), or of Rai stages 0-I (P=0.005). CD69 was confirmed to be an independent prognostic factor in multivariate analysis of progression free survival (P=0.017) and overall survival (P=0.039). ConclusionsOur data indicate that CD69 is significantly correlated with poor clinical and biological prognostic factors and is confirmed to be an independent disease prognosticator. This supports its introduction in a routine laboratory assessment and, possibly, in a prognostic scoring system for chronic lymphocytic leukemia, after an adequate standardization process.

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Section: Discussionsupporting

confidence: 51%

Section: Ighv Mutation Analysismentioning

confidence: 99%

CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study

Poeta

Principe²,

Zucchetto³

et al. 2011

Haematologica

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“…The IgV H mutational status, available for 96 out of 115 cases, was exactly as described. 5,6 According to the standard cut-off of 2% deviation from the corresponding germ-line sequence, employed to discriminate between mutated (M) or unmutated (UM) IgV H gene configuration, 5,6 M B-CLLs have significantly longer survivals, as compared to UM cases, also in our series (P ¼ 2.7 Â 10 À5 , data not shown). Expression of CD38 and CD49d was analyzed by three-color immunofluorescence, as described previously, 4 by combining phycoerythrin-conjugated anti-CD38 or anti-CD49d monoclonal antibodies (mAbs) with fluorescein isothiocyanate-and allophycocyanin-conjugated anti-CD19 and anti-CD5 mAbs.…”

mentioning

confidence: 64%

CD49d in B-cell chronic lymphocytic leukemia: correlated expression with CD38 and prognostic relevance

Zucchetto

Bomben

et al. 2006

Leukemia

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“…The resulting cDNAs, checked for first strand synthesis, 22 were amplified using a mixture of sense primers annealing to either V H 1 through V H 6 leader sequences or 5'ends of V H 1-V H 6 FR1. Purified amplifications were cloned and a minimum of 10-20 colonies for each case were sequenced; CLL specific IGHV transcripts, identified by sharing the same CDR3 in multiple clones were analyzed for percent mutation, as previously described.…”

Section: Ighv Mutation Analysismentioning

confidence: 99%

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

Principe

Bittolo

et al. 2015

Haematologica

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In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules. ABSTRACT

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Mutational status of IgVH genes in B-cell chronic lymphocytic leukemia and prognosis: percent mutations or antigen-driven selection?

Cited by 21 publications

References 8 publications

CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study

CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study

CD49d in B-cell chronic lymphocytic leukemia: correlated expression with CD38 and prognostic relevance

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

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