Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia

Claus, Rainer; Lucas, David M.; Ruppert, Amy S.; Williams, Katie; Weng, Daniel; Patterson, Kara; Zucknick, Manuela; Oakes, Christopher C.; Rassenti, Laura Z.; Greaves, Andrew W.; Geyer, Susan; Wierda, William G.; Brown, Jennifer R.; Gribben, John G.; Barrientos, Jacqueline C.; Kanti, R.; Kay, Neil E.; Kipps, Thomas J.; Shields, Peter G.; Zhao, Weiqiang; Grever, Michael R.; Plass, Christoph; Byrd, John C.

doi:10.1182/blood-2014-02-555722

Cited by 60 publications

(48 citation statements)

References 32 publications

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“…Signaling capacity was measured as percentage intracellular Ca 21 [iCa 21 ] mobilization following stimulation. 13 Briefly, 10 7 PBMC/mL were incubated with 4 mM Fluo3-AM (Invitrogen, Paisley, United Kingdom) and 0.02% (vol/vol) Pluronic F-127 (Sigma, Poole, United Kingdom) for 30 minutes at 37°C.…”

Section: /Cd5mentioning

confidence: 99%

“…TTFT was used as primary end point, whereas OS was used as a secondary end point to avoid the chemotherapy and kinase inhibitors as confounders. We used our previous cutoffs of 50% and 5% to distinguish patients with high/low sIgM/D (MFI) or signaling capacity (iCa 21 mobilization %), respectively. 13 These cutoffs corresponded to the best cutoffs by receiver operating characteristic and Youden t tests when treatment was used as a state variable.…”

Section: Statistical Analyses and Clinical Association Studiesmentioning

confidence: 99%

“…[21][22][23][24][25][26] Genome-wide DNA methylation studies have uncovered 2 major methylation subtypes along with a third intermediate group. 23,25,27 These groups largely represent the degree of epigenetic programming experienced by the B cell of origin in CLL, and are termed low-, intermediate-, and high-programmed CLLs (LP-CLLs, IP-CLLs, and HP-CLLs, respectively).…”

Section: Introductionmentioning

confidence: 99%

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Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL

D’Avola

Drennan

Tracy

et al. 2016

Blood

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Key Points• High sIgM level is a potential key factor associated with poorer clinical outcome in CLL.• Genetic and epigenetic features influence sIgM levels and function in CLL.Chronic lymphocytic leukemia (CLL) with unmutated (U-CLL) or mutated (M-CLL) immunoglobulin gene heavy-chain variable region (IGHV) displays different states of anergy, indicated by reduced surface immunoglobulin M (sIgM) levels and signaling, consequent to chronic (super)antigen exposure. The subsets also differ in the incidence of high-risk genetic aberrations and in DNA methylation profile, preserved from the maturational status of the original cell. We focused on sIgM expression and function, measured as intracellular Ca 21 mobilization following stimulation, and probed correlations with clinical outcome. The relationship with genetic features and maturation status defined by DNA methylation of an 18-gene panel signature was then investigated. sIgM levels/signaling were higher and less variable in U-CLL than in M-CLL and correlated with disease progression between and within U-CLL and M-CLL. In U-CLL, increased levels/signaling associated with 112, del(17p) or NOTCH1 mutations. In M-CLL, there were fewer genetic lesions, although the methylation maturation status, generally higher than in U-CLL, varied and was increased in cases with lower sIgM levels/signaling. These features revealed heterogeneity in M-CLL and U-CLL with clear clinical correlations. Multivariate analyses with phenotype, genetic lesions, or DNA methylation maturation status identified high sIgM levels as a new potential independent factor for disease progression. Multiple influences on sIgM include the cell of origin, the clonal history of antigen encounter in vivo, and genetic damage. This simple marker compiles these different factors into an indicator worthy of further investigations for prediction of clinical behavior, particularly within the heterogeneous M-CLL subset. (Blood. 2016;128(6):816-826)

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Section: /Cd5mentioning

confidence: 99%

Section: Statistical Analyses and Clinical Association Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL

D’Avola

Drennan

Tracy

et al. 2016

Blood

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“…It has also been found to be expressed in some subsets of activated B cells and in normal B cells precursors (10,11). Expression of ZAP-70 in CLL B cells is associated with unmutated IgV H (12)(13)(14)(15) and contributes to a more aggressive clinical course, probably by enhancing B cell receptor signaling (16,17).…”

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confidence: 99%

“…Evaluation of the prognostic value of ZAP-70 and CD38 has been performed using different methods including reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, flow-cytometry and immunohistochemistry (17,20).…”

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confidence: 99%