CLL - Molecular Biology

Overview

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (88)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
CD38 4p15.32 ADPRC1, ADPRC 1 -CD38 and Chronic Lymphocytic Leukemia
339
ZAP70 2q12 SRK, STD, TZK, STCD, ZAP-70 -ZAP70 and Chronic Lymphocytic Leukemia
250
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and Chronic Lymphocytic Leukemia
246
CD19 16p11.2 B4, CVID3 -CD19 and Chronic Lymphocytic Leukemia
166
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 -IGH and Chronic Lymphocytic Leukemia
162
NOTCH1 9q34.3 hN1, AOS5, TAN1, AOVD1 -NOTCH1 and Chronic Lymphocytic Leukemia
129
ATM 11q22.3 AT1, ATA, ATC, ATD, ATE, ATDC, TEL1, TELO1 -ATM and Chronic Lymphocytic Leukemia
79
CD40 20q13.12 p50, Bp50, CDW40, TNFRSF5 -CD40 and Chronic Lymphocytic Leukemia
67
SF3B1 2q33.1 MDS, PRP10, Hsh155, PRPF10, SAP155, SF3b155 -SF3B1 and Chronic Lymphocytic Leukemia
52
CD79B 17q23.3 B29, IGB, AGM6 -CD79B and Chronic Lymphocytic Leukemia
38
BIRC3 11q22.2 AIP1, API2, MIHC, CIAP2, HAIP1, HIAP1, MALT2, RNF49, c-IAP2 -BIRC3 and Chronic Lymphocytic Leukemia
36
MCL1 1q21.2 TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1/EAT -MCL1 and Chronic Lymphocytic Leukemia
34
TCL1A 14q32.13 TCL1 -TCL1A and Chronic Lymphocytic Leukemia
30
CD22 19q13.12 SIGLEC2, SIGLEC-2 -CD22 and Chronic Lymphocytic Leukemia
26
SYK 9q22.2 p72-Syk -SYK and Chronic Lymphocytic Leukemia
25
MYD88 3p22.2 MYD88D -MYD88 and Chronic Lymphocytic Leukemia
25
CD79A 19q13.2 IGA, MB-1 -CD79A and Chronic Lymphocytic Leukemia
21
AICDA 12p13.31 AID, ARP2, CDA2, HIGM2, HEL-S-284 -AICDA and Chronic Lymphocytic Leukemia
19
LYN 8q12.1 JTK8, p53Lyn, p56Lyn -LYN and Chronic Lymphocytic Leukemia
18
BCL3 19q13.32 BCL4, D19S37 -BCL3 and Chronic Lymphocytic Leukemia
17
IGL 22q11.22 IGL@, IGLC6 -IGL and Chronic Lymphocytic Leukemia
16
DLEU2 13q14.2 1B4, DLB2, LEU2, BCMSUN, RFP2OS, MIR15AHG, TRIM13OS, LINC00022, NCRNA00022 -DLEU2 and Chronic Lymphocytic Leukemia
16
CD80 3q13.33 B7, BB1, B7-1, B7.1, LAB7, CD28LG, CD28LG1 -CD80 and Chronic Lymphocytic Leukemia
16
CD52 1p36.11 HE5, CDW52, EDDM5 -CD52 and Chronic Lymphocytic Leukemia
16
ITGA4 2q31.3 IA4, CD49D -ITGA4 and Chronic Lymphocytic Leukemia
15
ROR1 1p31.3 NTRKR1, dJ537F10.1 -ROR1 and Chronic Lymphocytic Leukemia
15
TNFRSF17 16p13.13 BCM, BCMA, CD269, TNFRSF13A -TNFRSF17 and Chronic Lymphocytic Leukemia
14
PMAIP1 18q21.32 APR, NOXA -PMAIP1 and Chronic Lymphocytic Leukemia
14
P2RX7 12q24 P2X7 -P2RX7 and Chronic Lymphocytic Leukemia
13
IL2 4q27 IL-2, TCGF, lymphokine -IL2 and Chronic Lymphocytic Leukemia
12
LEF1 4q25 LEF-1, TCF10, TCF7L3, TCF1ALPHA -LEF1 and Chronic Lymphocytic Leukemia
12
CD27 12p13.31 T14, S152, Tp55, TNFRSF7, S152. LPFS2 -CD27 and Chronic Lymphocytic Leukemia
11
BBC3 19q13.32 JFY1, PUMA, JFY-1 -BBC3 and Chronic Lymphocytic Leukemia
11
PIK3CD 1p36.22 APDS, PI3K, IMD14, p110D, P110DELTA -PIK3CD and Chronic Lymphocytic Leukemia
10
CCR7 17q21.2 BLR2, EBI1, CCR-7, CD197, CDw197, CMKBR7, CC-CKR-7 -CCR7 and Chronic Lymphocytic Leukemia
10
TNFSF13B 13q33.3 DTL, BAFF, BLYS, CD257, TALL1, THANK, ZTNF4, TALL-1, TNLG7A, TNFSF20 -TNFSF13B and Chronic Lymphocytic Leukemia
10
BCL11A 2p16.1 EVI9, CTIP1, ZNF856, HBFQTL5, BCL11A-L, BCL11A-S, BCL11a-M, BCL11A-XL -BCL11A and Chronic Lymphocytic Leukemia
10
IRF4 6p25.3 MUM1, LSIRF, SHEP8, NF-EM5 -IRF4 and Chronic Lymphocytic Leukemia
10
TLR9 3p21.2 CD289 -TLR9 and Chronic Lymphocytic Leukemia
10
PRAME 22q11.22 MAPE, OIP4, CT130, OIP-4 -PRAME and Chronic Lymphocytic Leukemia
9
DAPK2 15q22.31 DRP1, DRP-1 -DAPK2 and Chronic Lymphocytic Leukemia
8
IL21 4q27 Za11, IL-21, CVID11 -IL21 and Chronic Lymphocytic Leukemia
8
CD86 3q13.33 B70, B7-2, B7.2, LAB72, CD28LG2 -CD86 and Chronic Lymphocytic Leukemia
8
POT1 7q31.33 GLM9, CMM10, HPOT1 -POT1 and Chronic Lymphocytic Leukemia
7
CCL3 17q12 MIP1A, SCYA3, G0S19-1, LD78ALPHA, MIP-1-alpha -CCL3 and Chronic Lymphocytic Leukemia
7
CD69 12p13.31 AIM, EA1, MLR-3, CLEC2C, GP32/28, BL-AC/P26 -CD69 and Chronic Lymphocytic Leukemia
7
CD1D 1q23.1 R3, CD1A, R3G1 -CD1D and Chronic Lymphocytic Leukemia
7
TNFSF13 17p13.1 APRIL, CD256, TALL2, ZTNF2, TALL-2, TNLG7B, TRDL-1, UNQ383/PRO715 -TNFSF13 and Chronic Lymphocytic Leukemia
6
DAPK1 9q21.33 DAPK -DAPK1 and Chronic Lymphocytic Leukemia
6
FBXW7 4q31.3 AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 -FBXW7 mutations in CLL
6
LTA 6p21.33 LT, TNFB, TNFSF1, TNLG1E -LTA and Chronic Lymphocytic Leukemia
5
CCL4 17q12 ACT2, G-26, HC21, LAG1, LAG-1, MIP1B, SCYA2, SCYA4, MIP1B1, AT744.1, MIP-1-beta -CCL4 and Chronic Lymphocytic Leukemia
5
CD74 5q33.1 II, DHLAG, HLADG, Ia-GAMMA -CD74 and Chronic Lymphocytic Leukemia
5
CDR2 16p12.2 Yo, CDR62 -CDR2 and Chronic Lymphocytic Leukemia
5
CXCR5 11q23.3 BLR1, CD185, MDR15 -CXCR5 and Chronic Lymphocytic Leukemia
5
ADAM29 4q34.1 CT73, svph1 -ADAM29 and Chronic Lymphocytic Leukemia
5
CD200 3q13.2 MRC, MOX1, MOX2, OX-2 -CD200 and Chronic Lymphocytic Leukemia
5
B2M 15q21.1 IMD43 -B2M and Chronic Lymphocytic Leukemia
5
CXCL9 4q21.1 CMK, MIG, Humig, SCYB9, crg-10 -CXCL9 and Chronic Lymphocytic Leukemia
5
CMBL 5p15.2 JS-1 -CMBL and Chronic Lymphocytic Leukemia
5
CD81 11p15.5 S5.7, CVID6, TAPA1, TSPAN28 -CD81 and Chronic Lymphocytic Leukemia
4
RHOH 4p14 TTF, ARHH -RHOH and Chronic Lymphocytic Leukemia
4
XPO1 2p15 emb, CRM1, exp1 -XPO1 and Chronic Lymphocytic Leukemia
4
CRY1 12q23.3 PHLL1 -CRY1 and Chronic Lymphocytic Leukemia
4
ARL11 13q14.2 ARLTS1 -ARL11 and Chronic Lymphocytic Leukemia
4
PAPPA 9q33.1 PAPA, DIPLA1, PAPP-A, PAPPA1, ASBABP2, IGFBP-4ase -PAPPA and Chronic Lymphocytic Leukemia
4
CCL17 16q21 TARC, ABCD-2, SCYA17, A-152E5.3 -CCL17 and Chronic Lymphocytic Leukemia
4
IL16 15q25.1 LCF, NIL16, PRIL16, prIL-16 -IL16 and Chronic Lymphocytic Leukemia
3
LAMP1 13q34 LAMPA, CD107a, LGP120 -LAMP1 and Chronic Lymphocytic Leukemia
3
TLR7 Xp22.2 TLR7-like -TLR7 and Chronic Lymphocytic Leukemia
3
MIR34A 1p36.22 mir-34, MIRN34A, mir-34a, miRNA34A -MIR34A and Chronic Lymphocytic Leukemia
3
BOLL 2q33 BOULE -BOLL and Chronic Lymphocytic Leukemia
3
UGT2B17 4q13.2 BMND12, UDPGT2B17 -UGT2B17 and Chronic Lymphocytic Leukemia
3
BCL11B 14q32.2 ATL1, RIT1, CTIP2, IMD49, CTIP-2, ZNF856B, ATL1-beta, ATL1-alpha, ATL1-delta, ATL1-gamma, hRIT1-alpha -BCL11B and Chronic Lymphocytic Leukemia
3
CCL19 9p13.3 ELC, CKb11, MIP3B, MIP-3b, SCYA19 -CCL19 and Chronic Lymphocytic Leukemia
3
POLI 18q21.2 RAD30B, RAD3OB -POLI and Chronic Lymphocytic Leukemia
2
TRIM13 13q14.2 CAR, LEU5, RFP2, DLEU5, RNF77 -TRIM13 and Chronic Lymphocytic Leukemia
2
ITGB2 21q22.3 LAD, CD18, MF17, MFI7, LCAMB, LFA-1, MAC-1 -ITGB2 and Chronic Lymphocytic Leukemia
2
MYBL1 8q13.1 AMYB, A-MYB -MYBL1 and Chronic Lymphocytic Leukemia
1
LTB 6p21.33 p33, TNFC, TNFSF3, TNLG1C -LTB and Chronic Lymphocytic Leukemia
1
ROR2 9q22.31 BDB, BDB1, NTRKR2 -ROR2 and Chronic Lymphocytic Leukemia
1
ETV3 1q23.1 PE1, METS, PE-1 -ETV3 and Chronic Lymphocytic Leukemia
1
TCL6 14q32.13 TNG1, TNG2 -TCL6 and Chronic Lymphocytic Leukemia
1
MS4A1 11q12.2 B1, S7, Bp35, CD20, CVID5, MS4A2, LEU-16 -MS4A1 and Chronic Lymphocytic Leukemia
1
ITGAL 16p11.2 CD11A, LFA-1, LFA1A -ITGAL and Chronic Lymphocytic Leukemia
1
SLAMF1 1q23.3 SLAM, CD150, CDw150 -SLAMF1 and Chronic Lymphocytic Leukemia
1
MIR125A 19q13.41 MIRN125A, mir-125a, miRNA125A -MIR125A and Chronic Lymphocytic Leukemia
1
ITGAX 16p11.2 CD11C, SLEB6 -ITGAX and Chronic Lymphocytic Leukemia

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Li XT, Zhu HY, Wang L, et al.
[Survival analysis of 118 chronic lymphocytic leukemia patients with abnormal TP53 gene in the era of traditional immunochemotherapy].
Zhonghua Xue Ye Xue Za Zhi. 2019; 40(5):378-383 [PubMed] Related Publications

Ioannidou A, Zachaki S, Daraki A, et al.
Paraoxonase 1 (PON1) Q192R and L55M Polymorphisms as Potential Predisposition Factors for Chronic Lymphocytic Leukemia.
Anticancer Res. 2019; 39(6):2861-2869 [PubMed] Related Publications
BACKGROUND/AIM: PON1 gene has an executive role in antioxidant defense, protecting cells from genotoxic factors. Q192R and L55M PON1 polymorphisms reduce catalytic activity of the encoded protein. These polymorphisms were studied in 300 chronic lymphocytic leukemia (CLL) patients and 106 healthy donors. They were also associated with patients' cytogenetic findings, to investigate their possible implication in CLL pathogenesis.
MATERIALS AND METHODS: SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Karyotypic analysis was also performed by chromosome G-banding analysis and fluorescence in situ hybridization.
RESULTS: Genotypic and allelic distribution of Q192R polymorphism showed a statistically significant higher frequency of mutant genotypes and mutant alleles in patients compared to controls. The same observation was noted in patients with abnormal karyotypes and those carrying abn14q32 and del(6q). A statistically increased frequency for the mutant allele was also revealed in patients with del(11q). On the contrary, L55M polymorphism showed a similar distribution between patients and controls.
CONCLUSION: Q192R polymorphism plays a role in CLL predisposition and the formation of specific chromosomal aberrations.

Michalová Z, Čoma M, Kičová M, et al.
Overexpression of Galectin-3 in Chronic Lymphocytic Leukemia Is Associated With 17p Deletion: A Short Report.
Anticancer Res. 2019; 39(6):2805-2810 [PubMed] Related Publications
BACKGROUND/AIM: Galectins belong to the family of galactose-binding proteins known to play an important role in the processes of cell proliferation, differentiation, migration and neoplastic progression. Herein, we studied the expression of galectin-3 (Gal-3) in chronic lymphocytic leukemia (CLL).
MATERIALS AND METHODS: The expression of Gal-3 was analyzed by means of multiparametric flow cytometry in normal and pathological B-cells from peripheral blood and bone marrow samples of 67 patients with CLL.
RESULTS: Pathological B-cells expressed significantly higher levels of cytoplasmic Gal-3 than normal B-cells. Moreover, overexpression of cytoplasmic Gal-3 was observed in the prognostically poorest subgroup of CLL patients, namely those with 17p deletion.
CONCLUSION: Our results indicate a possible role of galectin-3 in CLL pathophysiology and its potential value as a prognostic marker and therapeutic target.

Pastore A, Gaiti F, Lu SX, et al.
Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL.
Nat Commun. 2019; 10(1):1874 [PubMed] Free Access to Full Article Related Publications
Cancer evolution is fueled by epigenetic as well as genetic diversity. In chronic lymphocytic leukemia (CLL), intra-tumoral DNA methylation (DNAme) heterogeneity empowers evolution. Here, to comprehensively study the epigenetic dimension of cancer evolution, we integrate DNAme analysis with histone modification mapping and single cell analyses of RNA expression and DNAme in 22 primary CLL and 13 healthy donor B lymphocyte samples. Our data reveal corrupted coherence across different layers of the CLL epigenome. This manifests in decreased mutual information across epigenetic modifications and gene expression attributed to cell-to-cell heterogeneity. Disrupted epigenetic-transcriptional coordination in CLL is also reflected in the dysregulation of the transcriptional output as a function of the combinatorial chromatin states, including incomplete Polycomb-mediated gene silencing. Notably, we observe unexpected co-mapping of typically mutually exclusive activating and repressing histone modifications, suggestive of intra-tumoral epigenetic diversity. Thus, CLL epigenetic diversification leads to decreased coordination across layers of epigenetic information, likely reflecting an admixture of cells with diverging cellular identities.

Alsagaby SA
Transcriptomics-based validation of the relatedness of heterogeneous nuclear ribonucleoproteins to chronic lymphocytic leukemia as potential biomarkers of the disease aggressiveness.
Saudi Med J. 2019; 40(4):328-338 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To use independent transcriptomics data sets of cancer patients with prognostic information from public repositories to validate the relevance of our previously described chronic lymphocytic leukemia (CLL)-related proteins at the level of transcription (mRNA) to the prognosis of CLL.  Methods: This is a validation study that was conducted at Majmaah University, Kingdom of Saudi Arabia between January-2017 and July-2018. Two independent data sets of CLL transcriptomics from Gene Expression Omnibus (GEO) with time-to-first treatment (TTFT) data (GSE39671; 130 patients) and information about overall survival (OS) (GSE22762; 107 patients) were used for the validation analyses. To further investigate the relatedness of a transcript of interest to other neoplasms, 6 independent data sets of cancer transcriptomics with prognostic information (1865 patients) from the cancer genomics atlas (TCGA) were used. Pathway-enrichment analyses were conducted using Reactome; and correlation analyses of gene expression were performed using Pearson score. Results: Nine of the CLL-related proteins exhibited transcript expression that predicted TTFT and 7 of the CLL-related proteins showed mRNA levels that predicted OS in CLL patients (p≤0.05). Of these transcripts, 8 were different types of heterogeneous nuclear ribonucleoproteins (HNRNPs); and 2 (HNRNPUL2 and HIST1C1H) retained prognostic significance in the 2 independent data sets. Furthermore, genes that enriched CLL-related pathways (p≤0.05; false discovery rate [FDR] ≤0.05) were found to correlate with the expression of HNRNPUL2 (Pearson score: ≥0.50; p lessthan 0.00001). Finally, increased expression of HNRNPUL2 was indicative of poor prognosis of various types of cancer other than CLL (p less than 0.05). Conclusion: The cognate transcripts of 14 of our CLL-related proteins significantly predicted CLL prognosis.

Alsagaby SA, Alhumaydhi FA
Proteomics insights into the pathology and prognosis of chronic lymphocytic leukemia.
Saudi Med J. 2019; 40(4):317-327 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) is an incurable malignant disease of B-lymphocytes characterized by drastically heterogeneous clinical courses. Proteomics is an advanced approach that allows a global profiling of protein expression, providing a valuable chance for the discovery of disease-related proteins. In the last 2 decades, several proteomics studies were conducted on CLL to identify aberrant protein expression underpinning the malignant transformation and progression of the disease. Overall, these studies provided insights into the pathology and prognosis of CLL and reveal protein candidates with the potential to serve as biomarkers and/or therapeutic targets of the tumor. The major findings reported in these studies are discussed here.

Bilous N, Abramenko I, Chumak A, et al.
Analysis of LPL gene expression in patients with chronic lymphocytic leukemia.
Exp Oncol. 2019; 41(1):39-45 [PubMed] Related Publications
AIM: The IGHV mutational status is one of the most important markers for chronic lymphocytic leukemia (CLL) prognostication. Lipoprotein lipase (LPL) gene expression was found to correlate with IGHV status and was suggested as its surrogate marker. Recent data reported that LPL expression might be influenced by pivotal signalling pathways in CLL. This study aimed to assess LPL gene expression in relation to key immunogenetic and molecular markers of CLL, including IGHV mutational status, B-cell receptor (BCR) stereotypy, TP53, NOTCH1, and SF3B1 gene mutations. Materials and Methods: Expression of LPL mRNA was measured in peripheral blood mononuclear cells of 73 CLL patients by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). IGHV, NOTCH1, TP53, and SF3B1 gene mutation analysis was performed by PCR amplification and direct sequencing.
RESULTS: 44 of 73 (60%) CLL cases were categorized as LPL-positive based on the cut-off value established by ROC (receiver operating characteristic) curve analysis. LPL expression was significantly associated with IGHV mutation status (r = 0.684; p < 0.0001) and tended to correlate with presence of NOTCH1 gene mutations (p = 0.113). BCR stereotyped cases showed higher LPL expression values in comparison to unstereotyped cases in the LPL-positive group of patients (p = 0.041). LPL expression was associated with a shorter overall survival in the entire СLL group (median 107 vs 143, p = 0.048) as well as in Binet A patients, albeit with borderline significance (median 139 vs not reached, p = 0.086).
CONCLUSION: LPL expression was found to be closely correlated with IGHV gene mutational status and overall survival, proving LPL as prognostic marker in CLL. Our results also indicate a possible relationship between aberrant expression of LPL and BCR- and NOTCH1-dependent signalling pathways.

Lin S, Liu Y, Goldin LR, et al.
Sex-related DNA methylation differences in B cell chronic lymphocytic leukemia.
Biol Sex Differ. 2019; 10(1):2 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Men are at higher risk of developing chronic lymphocytic leukemia (CLL) than women. DNA methylation has been shown to play important roles in a number of cancers. There are differences in the DNA methylation pattern between men and women. In this study, we investigated whether this contributes to the sex-related difference of B cell CLL risk.
METHODS: Using the HumanMethylation450 BeadChip, we profiled the genome-wide DNA methylation pattern of CD19
RESULTS: We identified 1043 sex-related differentially methylated positions (DMPs) related to CLL, 56 of which are located on autosomes and 987 on the X chromosome. Using published B cell RNA-sequencing data, we found 18 genes covered by the DMPs also have different expression levels in male and female CLL patients. Among them, TRIB1, an autosome gene, has been shown to promote tumor growth by suppressing apoptosis.
CONCLUSIONS: Our study represents the first epigenome-wide association study (EWAS) that investigates the sex-related differences in cancer, and indicated that DNA methylation differences might contribute to the sex-related difference in CLL risk.

Wernig-Zorc S, Yadav MP, Kopparapu PK, et al.
Global distribution of DNA hydroxymethylation and DNA methylation in chronic lymphocytic leukemia.
Epigenetics Chromatin. 2019; 12(1):4 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chronic lymphocytic leukemia (CLL) has been a good model system to understand the functional role of 5-methylcytosine (5-mC) in cancer progression. More recently, an oxidized form of 5-mC, 5-hydroxymethylcytosine (5-hmC) has gained lot of attention as a regulatory epigenetic modification with prognostic and diagnostic implications for several cancers. However, there is no global study exploring the role of 5-hydroxymethylcytosine (5-hmC) levels in CLL. Herein, using mass spectrometry and hMeDIP-sequencing, we analysed the dynamics of 5-hmC during B cell maturation and CLL pathogenesis.
RESULTS: We show that naïve B-cells had higher levels of 5-hmC and 5-mC compared to non-class switched and class-switched memory B-cells. We found a significant decrease in global 5-mC levels in CLL patients (n = 15) compared to naïve and memory B cells, with no changes detected between the CLL prognostic groups. On the other hand, global 5-hmC levels of CLL patients were similar to memory B cells and reduced compared to naïve B cells. Interestingly, 5-hmC levels were increased at regulatory regions such as gene-body, CpG island shores and shelves and 5-hmC distribution over the gene-body positively correlated with degree of transcriptional activity. Importantly, CLL samples showed aberrant 5-hmC and 5-mC pattern over gene-body compared to well-defined patterns in normal B-cells. Integrated analysis of 5-hmC and RNA-sequencing from CLL datasets identified three novel oncogenic drivers that could have potential roles in CLL development and progression.
CONCLUSIONS: Thus, our study suggests that the global loss of 5-hmC, accompanied by its significant increase at the gene regulatory regions, constitute a novel hallmark of CLL pathogenesis. Our combined analysis of 5-mC and 5-hmC sequencing provided insights into the potential role of 5-hmC in modulating gene expression changes during CLL pathogenesis.

Shoyele O, Gupta G
Synchronous Diagnosis of
Ann Clin Lab Sci. 2018; 48(6):790-796 [PubMed] Related Publications
The occurrence of

Went M, Sud A, Speedy H, et al.
Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.
Blood Cancer J. 2018; 9(1):1 [PubMed] Free Access to Full Article Related Publications
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R

Tari K, Shamsi Z, Reza Ghafari H, et al.
The role of the genetic abnormalities, epigenetic and microRNA in the prognosis of chronic lymphocytic leukemia.
Exp Oncol. 2018; 40(4):261-267 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

Orsini P, Impera L, Parciante E, et al.
Droplet digital PCR for the quantification of Alu methylation status in hematological malignancies.
Diagn Pathol. 2018; 13(1):98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Alu repeats, belonging to the Short Interspersed Repetitive Elements (SINEs) class, contain about 25% of CpG sites in the human genome. Alu sequences lie in gene-rich regions, so their methylation is an important transcriptional regulation mechanism. Aberrant Alu methylation has been associated with tumor aggressiveness, and also previously discussed in hematological malignancies, by applying different approaches. Moreover, today different techniques designed to measure global DNA methylation are focused on the methylation level of specific repeat elements. In this work we propose a new method of investigating Alu differential methylation, based on droplet digital PCR (ddPCR) technology.
METHODS: Forty-six patients with hematological neoplasms were included in the study: 30 patients affected by chronic lymphocytic leukemia, 7 patients with myelodysplastic syndromes at intermediate/high risk, according with the International Prognostic Scoring System, and 9 patients with myelomonocytic leukemia. Ten healthy donors were included as controls. Acute promyelocytic leukemia-derived NB4 cell line, either untreated or treated with decitabine (DEC) hypomethylating agent, was also analyzed. DNA samples were investigated for Alu methylation level by digestion of genomic DNA with isoschizomers with differential sensitivity to DNA methylation, followed by ddPCR.
RESULTS: Using ddPCR, a significant decrease of the global Alu methylation level in DNA extracted from NB4 cells treated with DEC, as compared to untreated cells, was observed. Moreover, comparing the global Alu methylation levels at diagnosis and after azacytidine (AZA) treatment in MDS patients, a statistically significant decrease of Alu sequences methylation after therapy as compared to diagnosis was evident. We also observed a significant decrease of the Alu methylation level in CLL patients compared to HD, and, finally, for CMML patients, a decrease of Alu sequences methylation was observed in patients harboring the SRSF2 hotspot gene mutation c.284C>D.
CONCLUSIONS: In our work, we propose a method to investigate Alu differential methylation based on ddPCR technology. This assay introduces ddPCR as a more sensitive and immediate technique for Alu methylation analysis. To date, this is the first application of ddPCR to study DNA repetitive elements. This approach may be useful to profile patients affected by hematologic malignancies for diagnostic/prognostic purpose.

Schubert M, Hackl H, Gassner FJ, et al.
Investigating epigenetic effects of activation-induced deaminase in chronic lymphocytic leukemia.
PLoS One. 2018; 13(12):e0208753 [PubMed] Free Access to Full Article Related Publications
Activation induced deaminase (AID) has two distinct and well defined roles, both relying on its deoxycytidine (dC) deaminating function: one as a DNA mutator and another in DNA demethylation. In chronic lymphocytic leukemia (CLL), AID was previously shown to be an independent negative prognostic factor. While there is substantial impact on DNA mutations, effects of AID on gene expression by promoter demethylation of disease related target genes in leukemia has not been addressed. To shed light on this question, we aimed at determining genome wide methylation changes as well as gene expression changes in response to AID expression in CLL. Although we found minor differences in individual methylation variable positions following AID expression, we could not find recurrent methylation changes of specific target sites or changes in global methylation.

Chun K, Wenger GD, Chaubey A, et al.
Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia.
Cancer Genet. 2018; 228-229:236-250 [PubMed] Related Publications
The prognostic role of cytogenetic analysis is well-established in B-cell chronic lymphocytic leukemia (CLL). Approximately 80% of patients have a cytogenetic aberration. Interphase FISH panels have been the gold standard for cytogenetic evaluation, but conventional cytogenetics allows detection of additional abnormalities, including translocations, complex karyotypes and multiple clones. Whole genome copy number assessment, currently performed by chromosomal microarray analysis (CMA), is particularly relevant in CLL for the following reasons: (1) copy number alterations (CNAs) represent key events with biologic and prognostic significance; (2) DNA from fresh samples is generally available; and (3) the tumor burden tends to be relatively high in peripheral blood. CMA also identifies novel copy number variants and copy-neutral loss-of-heterozygosity (CN-LOH), and can refine deletion breakpoints. The Cancer Genomics Consortium (CGC) Working Group for CLL has performed an extensive literature review to describe the evidence-based clinical utility of CMA in CLL. We provide suggestions for the integration of CMA into clinical use and list recurrent copy number alterations, regions of CN-LOH and mutated genes to aid in interpretation.

Kapelko-Słowik K, Dybko J, Grzymajło K, et al.
Expression of the PIM2 gene is associated with more aggressive clinical course in patients with chronic lymphocytic leukemia.
Adv Clin Exp Med. 2019; 28(3):391-396 [PubMed] Related Publications
BACKGROUND: The PIM2 gene belongs to the PIM family, which encodes serine/threonine kinases involved in cell survival and apoptosis. The relation between the expression of the PIM2 gene and the course of chronic lymphocytic leukemia (CLL) has not been fully determined.
OBJECTIVES: The aim of the study was to evaluate the role of the PIM2 gene as a marker of CLL malignancy and its importance as a predictive and prognostic factor.
MATERIAL AND METHODS: Sixty-seven patients, 35 females and 32 males, aged 49-90 years, with de novo CLL, and 14 healthy individuals were enrolled in the study. Expression of the PIM2 gene was analyzed using TaqMan RQ-PCR assay and western blot test.
RESULTS: Median PIM2 gene expression in CLL patients was higher than in controls. Patients with high expression of the PIM2 gene had shorter progression-free survival and time to first treatment than patients with low PIM2 expression. It was found that patients with CR had lower expression of the PIM2 gene than patients without complete remission (CR). Notably, associations between high PIM2 expression and rapid lymphocyte doubling time, the percentage of malignant lymphocytes with ZAP70 expression and the Rai stage were revealed.
CONCLUSIONS: We found that the PIM2 gene is associated with a more aggressive clinical course of CLL.

Agathangelidis A, Sutton LA, Hadzidimitriou A, et al.
Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation.
J Vis Exp. 2018; (141) [PubMed] Related Publications
During B cell maturation, the complex process of immunoglobulin (IG) gene V(D)J recombination coupled with somatic hypermutation (SHM) gives rise to a unique DNA sequence within each individual B cell. Since B cell malignancies result from the clonal expansion of a single cell, IG genes represent a unique molecular signature common to all the malignant cells within an individual patient; thus, IG gene rearrangements can be used as clonal markers. In addition to serving as an important clonal identifier, the IG gene sequence can act as a 'molecular timeline' since it is associated with specific developmental stages and hence reflects the history of the B cell involved in the neoplastic transformation. Moreover, for certain malignancies, in particular chronic lymphocytic leukemia (CLL), the IG gene sequence holds prognostic and potentially predictive capabilities. That said, extrapolating meaningful conclusions from IG gene sequence analysis would be impossible if robust methods and tools were not available to aid in their analysis. This article, drawing on the vast experience of the European Research Initiative on CLL (ERIC), details the technical aspects and essential requirements necessary to ensure reliable and reproducible IG gene sequence analysis in CLL, a test that is now recommended for all CLL patients prior to treatment. More specifically, the various analytical stages are described ranging from the identification of the clonotypic IG gene rearrangement and the determination of the nucleotide sequence to the accurate clinical interpretation of the IG gene sequence data.

Brown JR
Relapsed CLL: sequencing, combinations, and novel agents.
Hematology Am Soc Hematol Educ Program. 2018; 2018(1):248-255 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Although the therapy of chronic lymphocytic leukemia (CLL) has changed rapidly over the last 5 years, the key considerations in selecting a therapy for a previously treated patient with CLL continue to include the nature of the prior therapy and the duration of prior remission to that therapy, the prognostic features of the disease, and the health and comorbidities of the patient in question. For patients treated initially with chemoimmunotherapy, randomized trials have demonstrated the benefit of targeted therapy. Retrospective data suggest that ibrutinib is preferred as a first kinase inhibitor, whereas recent data with venetoclax and rituximab may challenge the choice of ibrutinib as a first novel agent in the relapsed setting. Data on sequencing of novel agents remain quite sparse, consisting of 1 prospective trial that demonstrated the efficacy of venetoclax in patients who have experienced progression with a kinase inhibitor, as well as a retrospective real-world analysis supporting this observation. Novel agents in advanced clinical development include primarily next-generation Bruton's tyrosine kinase and phosphatidylinositol 3-kinase δ inhibitors, with other classes still in phase 1 trials. Clinical trials of combination time-limited therapies with the goal of deep remission and discontinuation are also in progress.

Ott CJ, Federation AJ, Schwartz LS, et al.
Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia.
Cancer Cell. 2018; 34(6):982-995.e7 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Enhancer profiling is a powerful approach for discovering cis-regulatory elements that define the core transcriptional regulatory circuits of normal and malignant cells. Gene control through enhancer activity is often dominated by a subset of lineage-specific transcription factors. By integrating measures of chromatin accessibility and enrichment for H3K27 acetylation, we have generated regulatory landscapes of chronic lymphocytic leukemia (CLL) samples and representative cell lines. With super enhancer-based modeling of regulatory circuits and assessments of transcription factor dependencies, we discover that the essential super enhancer factor PAX5 dominates CLL regulatory nodes and is essential for CLL cell survival. Targeting enhancer signaling via BET bromodomain inhibition disrupts super enhancer-dependent gene expression with selective effects on CLL core regulatory circuitry, conferring potent anti-tumor activity.

Dvorak P, Lysak D, Vohradska P, Subrt I
Precise determination of primary cytogenetic abnormalities provides added value for stratification of chronic lymphocytic leukemia patients.
Neoplasma. 2019; 66(1):128-139 [PubMed] Related Publications
Cytogenetic analysis has become a standard procedure in the management of newly diagnosed chronic lymphocytic leukemia patients. Prognostic information is reported based on the presence of certain abnormalities and karyotype complexity after conventional karyotyping and/or fluorescence in situ hybridization (FISH). The information on cytogenetic abnormalities occurring in isolation is robust; however, the performance of patients with two or more cytogenetic abnormalities is heterogeneous and information is scarce. This retrospective study analyzed whether information on the precise determination of primary cytogenetic abnormalities can have some added value in terms of risk stratification in chronic lymphocytic leukemia (CLL) patients. The study cohort was 121 patients without the need to start treatment for CLL immediately after diagnosis but had completed initial cytogenetic analysis. Results from conventional karyotyping after stimulation of CLL cells and FISH analysis were combined. Risk stratification based purely on the determination of primary cytogenetic abnormalities was effective in CLL patients, with comparable results in stratification based on the presence of certain abnormalities and karyotype complexity. It is recommended that information on suspected primary abnormalities is included in cytogenetic reports, especially in patients with two or more abnormalities, because this can provide valuable additional information.

Liu H, Wang XM, Mao M, et al.
[The expression and prognostic significance of microRNA-34a in Uygur and Han patients with chronic lymphocytic leukemia in Xinjiang Uygur Autonomous Region in China].
Zhonghua Nei Ke Za Zhi. 2018; 57(12):922-925 [PubMed] Related Publications
To investigate the expression of microRNA-34a (miR-34a) in patients with chronic lymphocytic leukemia (CLL) in Xinjiang Uygur and Han nationalities and its prognostic significance. Our data showed that miR-34a expression in Uygur and Han CLL patients was significantly higher than that in their respective healthy controls, while miR-34a levels were similar between Uygur and Han patients. By comparing with known prognostic factors, receiver operating characteristic (ROC) curves showed that miR-34a was a good predictive factor for the prognosis of CLL (demarcation value was 3.567 6). Survival analysis was further performed according to miR-34a expression level, that low expression of miR-34a translated into poor prognosis.

Chen XL, Wang SF, Liang XT, et al.
SENP2 exerts an anti‑tumor effect on chronic lymphocytic leukemia cells through the inhibition of the Notch and NF‑κB signaling pathways.
Int J Oncol. 2019; 54(2):455-466 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Chronic lymphocytic leukemia (CLL) is one of the most often diagnosed hematological malignant tumors in the Western world and a type of inert B‑cell lymphoma that commonly attacks the elderly. Small ubiquitin related modifier (SUMO)‑specific protease 2 (SENP2) can act as a suppressor in various types of cancer by regulating the stability of β‑catenin to affect the Notch signaling pathway; however, it has a low expression level in CLL cells. In this study, we firstly used western blot analysis and RT‑qPCR to detect the protein and mRNA expression levels of SENP2 in the peripheral blood of patients with CLL and healthy volunteers. Secondly, we overexpressed or knocked down the expression of SENP2 in CLL cells and then determined the cell invasive and chemotactic ability in a Transwell assay and chemotaxis assay. We examined the sensitivity of the cells to cytarabine and dexamethasone via a CCK‑8 assay and determined the cell apoptotic condition and the expression of the Notch signaling pathway using flow cytometry and western blot analysis. The results demonstrated that the patients with CLL had relatively low expression levels of SENP2. The overexpression of SENP2 in the CLL cells decreased their invasive and proliferative ability, as well as their chemotactic response and enhanced their sensitivity to cytarabine and dexamethasone, while it promoted cell apoptosis. The silencing of SENP2 in the CLL cells generally produced the opposite results. We thus hypothesized that the overexpression of SENP2 downregulated β‑catenin expression, thus inhibiting the Notch signaling pathway in CLL cells. Moreover, the nuclear factor (NF)‑κB signaling pathway was also regulated by the overexpression of SENP2. On the whole, the findings of this study indicate tha SENP2 can act as a tumor suppressor in CLL cells, and may thus prove to be a novel target for CLL treatment in clinical practice.

Gao C, Zhou C, Zhuang J, et al.
Identification of key candidate genes and miRNA‑mRNA target pairs in chronic lymphocytic leukemia by integrated bioinformatics analysis.
Mol Med Rep. 2019; 19(1):362-374 [PubMed] Article available free on PMC after 10/12/2019 Related Publications
Chronic lymphocytic leukemia (CLL) is a malignant clonal proliferative disorder of B cells. Inhibition of cell apoptosis and cell cycle arrest are the main pathological causes of this disease, but its molecular mechanism requires further investigation. The purpose of the present study was to identify biomarkers for the early diagnosis and treatment of CLL, and to explore the molecular mechanisms of CLL progression. A total of 488 differentially expressed genes (DEGs) and 32 differentially expressed microRNAs (miRNAs; DEMs) for CLL were identified by analyzing the gene chips GSE22529, GSE39411 and GSE62137. Functional and pathway enrichment analyses of DEGs demonstrated that DEGs were mainly involved in transcriptional dysregulation and multiple signaling pathways, such as the nuclear factor‑κB and mitogen‑activated protein kinase signaling pathways. In addition, Cytoscape software was used to visualize the protein‑protein interactions of these DEGs in order to identify hub genes, which could be used as biomarkers for the early diagnosis and treatment of CLL. Cytoscape software was also used to analyze the association between the predicted target mRNAs of DEMs and DEGs and increase knowledge about the miRNA‑mRNA regulatory network associated with the progression of CLL. Taken together, the present study provided a bioinformatics basis for advancing our understanding of the pathogenesis of CLL by identifying differentially expressed hub genes, miRNA‑mRNA target pairs and molecular pathways. In addition, hub genes may be used as novel biomarkers for the diagnosis of CLL and to guide the selection of CLL drug combinations.

Zaprazna K, Reblova K, Svobodova V, et al.
Activation-induced deaminase and its splice variants associate with trisomy 12 in chronic lymphocytic leukemia.
Ann Hematol. 2019; 98(2):423-435 [PubMed] Related Publications
Activation-induced cytidine deaminase (AID) is a mutator enzyme essential for somatic hypermutation (SHM) and class switch recombination (CSR) during effective adaptive immune responses. Its aberrant expression and activity have been detected in lymphomas, leukemias, and solid tumors. In chronic lymphocytic leukemia (CLL) increased expression of alternatively spliced AID variants has been documented. We used real-time RT-PCR to quantify the expression of AID and its alternatively spliced transcripts (AIDΔE4a, AIDΔE4, AIDivs3, and AIDΔE3E4) in 149 CLL patients and correlated this expression to prognostic markers including recurrent chromosomal aberrations, the presence of complex karyotype, mutation status of the immunoglobulin heavy chain variable gene, and recurrent mutations. We report a previously unappreciated association between higher AID transcript levels and trisomy of chromosome 12. Functional analysis of AID splice variants revealed loss of their activity with respect to SHM, CSR, and induction of double-strand DNA breaks. In silico modeling provided insight into the molecular interactions and structural dynamics of wild-type AID and a shortened AID variant closely resembling AIDΔE4, confirming its loss-of-function phenotype.

Yuan YY, Zhu HY, Wu JZ, et al.
The percentage of cells with 17p deletion and the size of 17p deletion subclones show prognostic significance in chronic lymphocytic leukemia.
Genes Chromosomes Cancer. 2019; 58(1):43-51 [PubMed] Related Publications
TP53 disruption is considered to be the most important prognostic factor in chronic lymphocytic leukemia (CLL), but not all patients with TP53 disruption have similar dismal outcomes. We evaluated the prognostic value of TP53 disruption in CLL patients without treatment indications. Data of 305 CLL patients were analyzed. 41 of them (13%) had TP53 disruption. Patients with lower percentage of cells with del(17p) had significantly better survival. Patients with mutated IGHV, β2-microglobulin ≤3.5 mg/L, wild-type TP53, age ≤65 years or without complex karyotype (CK) had relatively favorable outcomes in the del(17p) group. Furthermore, patients with del(17p) as a minor clone showed survival advantage compared with those with del(17p) as a major clone. These data suggest that the percentage of cells with del(17p), the size of the del(17p) subclone, CLL International Prognostic Index, and CK should be considered to build refined prognostication models for patients with TP53 disruption.

Vlachonikola E, Vardi A, Stamatopoulos K, Hadzidimitriou A
High-Throughput Sequencing of the T-Cell Receptor Beta Chain Gene Repertoire in Chronic Lymphocytic Leukemia.
Methods Mol Biol. 2019; 1881:355-363 [PubMed] Related Publications
High-throughput, next-generation sequencing (NGS) offers a unique opportunity for in-depth characterization of adaptive immune receptor repertoires. Nevertheless, limitations and pitfalls exist in every step of both the experimental and the analytical procedure, leading to discrepancies in the literature and incomprehensive and/or altogether misleading results. Thus, standardization of protocols in NGS immunogenetics is urgently needed.Here, we describe the experimental protocol that we developed for T-cell receptor beta chain (TRB) gene repertoire analysis in chronic lymphocytic leukemia, aiming to provide a reproducible and biologically meaningful output. Although optimized for TRBV-TRBD-TRBJ gene rearrangements, this protocol may be customized for other adaptive immune receptor sequences, as well.

Parker H, Carr L, Syeda S, et al.
Characterization of Somatically-Acquired Copy Number Alterations in Chronic Lymphocytic Leukaemia Using Shallow Whole Genome Sequencing.
Methods Mol Biol. 2019; 1881:327-353 [PubMed] Related Publications
Shallow whole genome sequencing (sWGS) is a simple, robust, and cost-effective technique recently optimized for the identification of copy number aberrations (CNAs) in tumor samples. This multiplexed methodology sequences 50 bp from one end of the DNA molecule, generating ˜0.1× coverage, and utilizes the observed sequence depth across the genome to infer copy number. It is amenable to low quantities of input DNA, sequencing costs are modest, processing is compatible with low-output instruments, and downstream analysis is simplified by the use of freely available bioinformatics tools and a data analysis package written especially for the analysis of sWGS data. It is the aim of this chapter to introduce the fundamental concepts of sWGS and to provide an overview of the steps involved in a successful sWGS experiment.

Quesada V, Araujo-Voces M, Pérez-Silva JG, et al.
Genome Sequencing and Analysis Methods in Chronic Lymphocytic Leukemia.
Methods Mol Biol. 2019; 1881:319-325 [PubMed] Related Publications
The genomic sequencing of chronic lymphocytic leukemia (CLL) samples has provided exciting new venues for the understanding and treatment of this prevalent disease. This feat is possible thanks to high-throughput sequencing methods, such as Illumina sequencing. The interpretation of these data sources requires not only appropriate software and hardware, but also understanding the biology and technology behind the sequencing process. Here, we provide a primer to understand each step in the analysis of point mutations from whole-genome or whole-exome sequencing experiments of tumor and normal samples.

Murthy T, Paul KV, Minella AC, Pillai MM
The Development and Use of Scalable Systems for Studying Aberrant Splicing in SF3B1-Mutant CLL.
Methods Mol Biol. 2019; 1881:83-99 [PubMed] Related Publications
Mutational landscape of CLL is now known to include recurrent non-synonymous mutations in SF3B1, a core splicing factor. About 5-10% of newly diagnosed CLL harbor these mutations which are typically limited to HEAT domains in the carboxyl-terminus of the protein. Importantly, the mutations are not specific to CLL but also present in several unrelated clonal disorders. Analysis of patient samples and cell lines has shown the primary splicing aberration in SF3B1-mutant cells to the use of novel or "cryptic" 3' splice sites (3SS). Advances in genome-editing and next-generation sequencing (NGS) have allowed development of isogenic models and detailed analysis of changes to the transcriptome with relative ease. In this manuscript, we focus on two relevant methods to study splicing factor mutations in CLL: development of isogenic scalable cell lines and informatics analysis of RNA-Seq datasets.

Pavlova S, Smardova J, Tom N, Trbusek M
Detection and Functional Analysis of TP53 Mutations in CLL.
Methods Mol Biol. 2019; 1881:63-81 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) represents a prototype disease in which TP53 gene defects lead to inferior prognosis. Here, we present two distinct methodologies which can be used to identify TP53 mutations in CLL patients; both protocols are primarily intended for research purposes. The functional analysis of separated alleles in yeast (FASAY) can be flexibly adapted to a variable number of samples and provides an immediate functional readout of identified mutations. Amplicon-based next-generation sequencing then allows for a high throughput and accurately detects subclonal TP53 variants (sensitivity <1% of mutated cells).

Familial Clustering of Chronic Lymphocytic Leukaemia

There is a three-fold increase in risk of CLL in relatives of patients. There have been a number of reports that affected offspring are diagnosed with CLL at a younger age than their parents. Yuille (Leukemia, 1998) in a systematic study of 10 CLL families found that offspring were diagnosed an average of 22 years younger than their parents and offspring as consistent with other reports.

The cause(s) of familial clustering of CLL remain unknown, there might be environmental causes and/or genetic susceptibility. Bevan (Leukemia, 1999) found no evidence of linkage between ATM (the Ataxia Telangiectasia gene) and CLL in 24 CLL families. Payelle-Brogard (Blood, 1999) likewise found no evidence for common CD79b gene mutations in 10 CLL families.

Pritsch O, Troussard X, Magnac C, et al.
VH gene usage by family members affected with chronic lymphocytic leukaemia.
Br J Haematol. 1999; 107(3):616-24 [PubMed] Related Publications
The excess risk of chronic lymphocytic leukaemia (CLL) in the first-degree relatives of affected patients suggests that familial CLL might constitute a useful model to study the pathogenesis of this disease, as has been demonstrated in numerous other neoplastic disorders. Previous studies have shown non-random utilization of immunoglobulin genes in CLL, some germline in sequence and others containing numerous somatic mutations. To investigate whether familial cases of CLL exhibit similarities in the composition of the B-cell receptor repertoire to the pattern expressed by CLL patients as a whole, we have studied 25 CLL patients belonging to 12 different families (four French and eight Italian), each of which contained at least two affected members. Among familial cases, VH gene segment utilization proved non-random and diverged from the frequencies previously reported among unrelated patients with CLL. Specifically, although the 4-34 and 5-51 gene segments were found repeatedly, the 1-69 and 4-39 gene segments were used sparingly and the 3-23 gene segment presented with increased frequency. Following the pattern detected in studies of unrelated patients, the single 1-69 expressing CLL contained an unmutated H chain sequence and included a long HCDR3 interval. In contrast, 3-23 containing H chains all used JH4, retained at most 93% homology with germline sequence, and included only short HCDR3 intervals. The vast majority of the CLL variable domains contained a high degree of somatic mutation and exhibited an excess of replacement mutations in the CDR intervals. These findings suggest that familial CLL cases may preferentially derive from B-cell progenitors that have responded to antigen.

Yuille MR, Houlston RS, Catovsky D
Anticipation in familial chronic lymphocytic leukaemia.
Leukemia. 1998; 12(11):1696-8 [PubMed] Related Publications
A recent analysis of literature reports of familial clusters of chronic lymphocytic leukaemia (CLL) suggested that affected offspring are diagnosed at an age 21 years less than CLL parents. Such an analysis risks sampling bias. We avoided these potential sources of bias by systematic ascertainment of CLL families. Statistical analysis of 10 such families showed a significant decline of 22 years between the mean ages at diagnosis of disease in parents and offspring. This confirms the analysis of literature reports and provides the first systematic investigation of a phenomenon which, if familial clustering of CLL cases is considered due to genetic effects, points to familial CLL manifesting anticipation.

Payelle-Brogard B, Magnac C, Mauro FR, et al.
Analysis of the B-cell receptor B29 (CD79b) gene in familial chronic lymphocytic leukemia.
Blood. 1999; 94(10):3516-22 [PubMed] Related Publications
The B-cell antigen receptor (BCR) comprises membrane Igs (mIgs) and a heterodimer of Igalpha (CD79a) and Igbeta (CD79b) transmembrane proteins, encoded by the mb-1 and B29 genes, respectively. These accessory proteins are required for surface expression of mIg and BCR signaling. B cells from chronic lymphocytic leukemia (B-CLL) frequently express low to undetectable surface Ig, as well as CD79b protein. Recent work described genetic aberrations affecting B29 expression and/or function in B-CLL. Because the prevalence of CLL is increased among first degree relatives, we analyzed the B29 gene in 10 families including 2 affected members each. A few silent or replacement mutations were observed at the genomic level, which never lead to truncated CD79b protein. Both members of the same family did not harbor the same mutations. However, a single silent base change in the B29 extracellular domain, corresponding to a polymorphism, was detected on 1 allele of most patients. These results indicate that the few mutations observed in the B29 gene in these patients do not induce structural abnormalities of the CD79b protein and thus do not account for its low surface expression in B-CLL. Furthermore, genetic factors were not implicated, because identical mutations were not observed among 2 members of the same family.

Bevan S, Catovsky D, Marossy A, et al.
Linkage analysis for ATM in familial B cell chronic lymphocytic leukaemia.
Leukemia. 1999; 13(10):1497-500 [PubMed] Related Publications
B cell chronic lymphocytic leukaemia (CLL) shows evidence of familial aggregation, but the inherited basis is poorly understood. Mutations in the ATM gene have been demonstrated in CLL. This, coupled with a possibly increased risk of leukaemia in relatives of patients with Ataxia Telangiectasia, led us to question whether the ATM gene is involved in familial cases of CLL. To examine this proposition we typed five markers on chromosome 11q in 24 CLL families. No evidence for linkage between CLL and ATM in the 24 families studied and the best estimates of the proportion of sibling pairs that share no, one or both haplotypes at ATM were not different from their null expectations. This would imply that ATM is unlikely to make a significant contribution to the three-fold increase in risk of CLL seen in relatives of patients.

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