Monoclonal B-cell lymphocytosis is characterized by mutations in CLL putative driver genes and clonal heterogeneity many years before disease progression

Ojha, Juhi; Secreto, Charla; Rabe, Kari G.; Ayres-Silva, Jackline de Paula; Tschumper, Renee C.; Dyke, Daniel Van; Slager, Susan L.; Fonseca, Rafaël; Shanafelt, Tait D.; Kay, Neil E.; Braggio, Esteban

doi:10.1038/leu.2014.226

Cited by 46 publications

(40 citation statements)

References 15 publications

(16 reference statements)

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“…62 Although only a small number of MBL cases have been characterized by whole-exome sequencing, a broad heterogeneous spectrum of mutations are clearly present in MBL (including SF3B1, NOTCH1, FBXW7, and DDX3X), similar to the mutational spectrum of CLL. 63 In the majority of cases reported thus far, trisomy 12 and del(13q) were also detected by fluorescence in situ hybridization, supporting the idea that these are early lesions in CLL.…”

Section: Blood 23 July 2015 X Volume 126 Number 4 Genomic and Epigesupporting

confidence: 49%

Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

Guièze

2015

Blood

129

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Defining features of chronic lymphocytic leukemia (CLL) are not only its immunophenotype of CD19+CD5+CD23+sIgdim expressing clonal mature B cells but also its highly variable clinical course. In recent years, advances in massively parallel sequencing technologies have led to rapid progress in our understanding of the CLL genome and epigenome. Overall, these studies have clearly demarcated not only the vast degree of genetic and epigenetic heterogeneity among individuals with CLL but also even within individual patient leukemias. We herein review the rapidly growing series of studies assessing the genetic and epigenetic features of CLL within clinically defined periods of its growth. These studies strongly suggest an evolving spectrum of lesions over time and that these features may have clinical impact.

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Section: Blood 23 July 2015 X Volume 126 Number 4 Genomic and Epigesupporting

confidence: 49%

Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

Guièze

2015

Blood

129

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“…We found no difference in the frequency of genomic mutations or any other biomarker, apart from a border-line higher incidence of CD38 expression in cMBL, between cases presenting with cMBL or stage A CLL. This is consistent with other recent data confirming the biological similarity between cMBL and Rai O CLL, including a similar incidence of NOTCH1 and SF3B1 mutations, 6 and provides justification for analyzing the outcome of the combined cMBL and stage A cohorts.…”

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confidence: 79%

Low frequency mutations independently predict poor treatment-free survival in early stage chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

et al. 2015

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“…(21, 22) We performed the first comprehensive, whole exome sequencing (WES) study sequentially evaluating eight high-count MBLs at two time points. (23) The study detected mutations in putative CLL driver genes in half of the cases and confirmed the existence of clonal heterogeneity at a median of 5 years before progression to CLL. (23) Another recent study employed whole genome sequencing identified a similar overall mutation burden between MBL and CLL, but with a significantly lower number of affected driver genes in MBL.…”

Section: Introductionmentioning

confidence: 60%

Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome

et al. 2016

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High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B-cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biologic events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep-sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs(52%) at the initial time-point analyzed, including 13(27%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time-point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution have prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.

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Monoclonal B-cell lymphocytosis is characterized by mutations in CLL putative driver genes and clonal heterogeneity many years before disease progression

Cited by 46 publications

References 15 publications

Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

Low frequency mutations independently predict poor treatment-free survival in early stage chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome

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