The cellular origin and malignant transformation of Waldenström macroglobulinemia

Abstract

Key Points• Benign (ie, IgM MGUS and smoldering WM) clonal B cells already harbor the phenotypic and molecular signatures of the malignant WM clone.• Multistep transformation from benign (ie, IgM MGUS and smoldering WM) to malignant WM may require specific copy number abnormalities.Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n 5 22), smoldering (n 5 16), and symptomatic WM (n 5 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25 2 CD22 1 B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25 1 CD221low ) B-cell counterpart. The frequency of specific copy number abnormalities [14, del(6q23.3-6q25.3), 112, and 118q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P 5 .008), suggesting a multistep transformation of clonal B cells that, albeit benign (ie, IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström clone. (Blood. 2015;125(15):2370-2380

WM, MYD88, and CXCR4: following the thread

“…The lack of similarity between WM and normal memory B cells raises the possibility of a different cell of origin of the WM cell than previously thought. 8 However, it could also reflect the heterogeneity that is increasingly being discovered in the memory B-cell compartment. Genomic subclassification of WM.…”

Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis

“…The AGCC and ChAS software programs (Affymetrix) were used for data analysis, as described elsewhere. 12,13 Full microarray data are available at the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/; accession number GSE73042). Fluorescence in-situ hybridization (FISH) investigating IGH translocations and del(17p13) was also performed; del(13q14) was tested in selected cases.…”

“…standford.edu/;tibs/SAM) and the lowest q-value (,10 25 ). 12 Genome-wide detection of CNAs and copy number-neutral (CNN) loss-ofheterozygosity (LOH) were investigated using the Cytoscan 750K platform (Affymetrix) in 11 of 24 cases, with adequate DNA extracted from FACS-sorted clonal PCs. Given that matched normal DNA was only available in a subset of cases (n 5 7/11), an unpaired analysis was performed using 240 Hapmap files.…”

“…Data acquisition was performed in a FACS Canto II flow cytometer (Becton Dickinson Biosciences [BD], San Jose, CA) using the FACSDiva 6.1 software (BD). Generation of immunophenotypic protein expression profiles (iPEP) based on the 12 different markers evaluated at the single-cell level was performed as described elsewhere 12 using the Infinicyt software (Cytognos SL, Salamanca, Spain).…”

“…RNA was retrotranscribed into cDNA and hybridized to the Human Gene 1.0 ST Array (Affymetrix, Santa Clara, CA); normalization of the measured data was done using the expression console (Affymetrix) and the RMA algorithm, which includes background correction, normalization, and calculation of expression (log2) values. 12 Differentially expressed genes between classes were identified using the Significant Analysis of Microarrays algorithm (http://www.statweb. standford.edu/;tibs/SAM) and the lowest q-value (,10 25 ).…”