Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia

Rassenti, Laura Z.; Jain, Sonia; Keating, Michael J.; Wierda, William G.; Grever, Michael R.; Byrd, John C.; Kay, Neil E.; Brown, Jennifer R.; Gribben, John G.; Neuberg, Donna; He, Feng; Greaves, Andrew W.; Kanti, R.; Kipps, Thomas J.

doi:10.1182/blood-2007-05-092882

Cited by 294 publications

(231 citation statements)

References 46 publications

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“…For cellular and serum miR-150 cutoff determina-tion, recursive partitioning to maximize treatment-free survival (TFS)/overall survival (OS) prediction was used. These two techniques for cutoff determination, previously described (23,27), give similar results with some differences because IgHV mutational status does not perfectly predict TFS/OS. The association between microRNA expression and Binet stage was assessed by the Kruskal-Wallis test, and the MannWhitney nonparametric test was used for other variables.…”

Section: Discussionmentioning

confidence: 85%

Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

Stamatopoulos

Damme

Crompot

et al. 2015

Mol Med

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Recently, extracellular circulating microRNAs were also detected in body fluids, such as serum, plasma, saliva and urine (7). These circulating microRNAs are believed to be chaperoned by various carriers, such as secreted mem- MicroRNAs (or miRs) play a crucial role in chronic lymphocytic leukemia (CLL) physiopathology and prognosis. In addition, circulating microRNAs in body fluids have been proposed as new biomarkers. We investigated the expression of matched cellular and serum circulating microRNA-150 by quantitative real-time PCR (qPCR) from purified CD19 + cells or from CLL serums obtained at diagnosis in a cohort of 273/252 CLL patients with a median follow-up of 78 months (range 7-380) and correlated it to other biological or clinical parameters. We showed that miR-150 was significantly overexpressed in CLL cells/serums compared with healthy subjects (P < 0.0001). Among CLL patients, a low cellular miR-150 expression level was associated with tumor burden, disease aggressiveness and poor prognostic factors. In contrast, a high level of serum miR-150 was associated with tumor burden markers and some markers of poor prognosis. Similarly, cellular and serum miR-150 also predicted treatment-free survival (TFS) and overall survival (OS) in an opposite manner: patients with low cellular/serum miR-150 levels have median TFS of 40/111 months compared with high-level patients who have a median TFS of 122/60 months (P < 0.0001/P = 0.0066). Similar results were observed for OS. We also found that cellular and serum miR-150 levels vary in an opposite manner during disease progression and that cellular miR-150 could be regulated by its release into the extracellular space. Cellular and serum levels of miR-150 are associated with opposite clinical prognoses and could be used to molecularly monitor disease evolution as a new prognostic factor in CLL. brane vesicles (exosomes from 50 to 100 nm and microvesicles from 100 nm to 1 μm) or protein/lipid complexes (8,9), since carrier-free microRNAs will be degraded by RNase digestion and other environmental factors (9). Their levels and composition have been shown to be modulated with injury conditions as well as tumor burden (10-12). For these reasons, extracellular microRNAs could be used as informative biomarkers to assess and monitor disease evolution (11,13). Moussay et al. (14) recently observed that some circulating microRNAs in CLL plasma could be used as prognostic factors. Among these, microRNA-150 warranted further investigation for a number of reasons. This microRNA plays an important role in normal and malignant hematopoiesis (15). In addition, plasma (14) and cellular (16,17) microRNA-150 were both downregulated in poor prognosis CLL patients based on ZAP70 and IgHV mutational status. A low level of cellular microRNA-150 was also observed in CLL proliferation centers (18), and microRNA-150 is differentially expressed according to the stereotyped B-cell receptor (BCR) subset taken into consideration (19), emphasizing its pivotal role in CLL. Finally, a recent s...

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Section: Discussionmentioning

confidence: 85%

Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

Stamatopoulos

Damme

Crompot

et al. 2015

Mol Med

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“…The poorer outcome of patients with more than one risk factor is also seen in stage A patients among whom those with more than one adverse risk factor have a shorter treatment-free survival. [31][32][33] A number of important conclusions can be drawn from this study. Firstly, the poor outcome of patients with 17p loss treated with alkylator/purine analog therapy is confirmed, supporting the need to screen patients for a TP53 abnormality prior to initial therapy.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 79%

Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation

Oscier

Wade²,

Davis³

et al. 2010

Haematologica

115

108

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“…Zap-70 and CD38 expression and cytogenetic abnormalities involving deletions at chromosomes 11q23, 13q14, 17p13, and trisomy 12 were evaluated as previously described [11,12].…”

Section: Treatmentmentioning

confidence: 99%

Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia

et al. 2013

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The immunoglobulin heavy chain variable (IGHV) gene mutational status represents a major prognostic marker in chronic lymphocytic leukemia (CLL). Usually, the prognostic implications of IGHV gene analysis can be reliably ascertained but, occasionally, double productive rearrangements have been detected. Clinical presentation and biological features of such cases are unknown. Sixty patients with morphologically and phenotypically monoclonal CLL but double productive IGHV rearrangements were retrospectively identified by mRNA analysis from three Hematology Institutions. Clinical and biological features and survival of these 60 patients were compared with a control group of patients with CLL and single IGHV rearrangement. A prospective registry was used to assess the epidemiology of double productive IGHV among incidental patients with CLL. Using standard criteria to define IGHV-mutated (M) or unmutated (U) cases, 39 of the 60 patients (65%) with double productive IGHV rearrangement had concordant status (23 MM, 16 UU), while 21 (35%) had discordant IGHV status. As compared with M patients, the MM ones had lower CD38 expression, more favorable cytogenetics and more indolent clinical behavior. Cases with UU had similar characteristics of U patients. Discordant cases presented with adverse prognostic features and had an aggressive clinical behavior requiring early treatment, similar to U patients. The prevalence of double IGHV was 3.1%. Patients with CLL with double concordant mutational status (MM or UU) have a clinical course similar to that of the corresponding single IGHV status, while those exhibiting discordant status represent a high risk population. This may help correct stratification within clinical trials. Am.

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Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia

Cited by 294 publications

References 46 publications

Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation

Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia

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