CLL - Molecular Biology

Overview

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Gene Expression Profiling
  • Chromosome Deletion
  • SF3B1
  • Immunoglobulin Heavy Chains
  • TCL1A
  • Genetic Predisposition
  • MCL1
  • High-Throughput Nucleotide Sequencing
  • CD40
  • Chronic Lymphocytic Leukemia
  • Neoplasm Proteins
  • BCL11A
  • Drug Resistance
  • Disease Progression
  • Staging
  • Chromosome Aberrations
  • Biomarkers, Tumor
  • DNA Methylation
  • Stromal Cells
  • DNA Mutational Analysis
  • MYD88
  • Phosphoproteins
  • Single Nucleotide Polymorphism
  • Tumor Burden
  • p53 Protein
  • Antineoplastic Agents
  • Cell Proliferation
  • Case-Control Studies
  • PMAIP1
  • LEF1
  • CD22
  • BCL3
  • Immunoglobulin Variable Region
  • Apoptosis
  • DNA Sequence Analysis
  • FISH
  • Paraffin Embedding
  • Receptors, Antigen
  • Leukemic Gene Expression Regulation
  • Mutation
  • Transcriptome
  • ATM
  • Cohort Studies
  • Tetraspanins
  • Spliceosomes
  • Transcription
  • RT-PCR
  • BIRC3
  • Cancer Gene Expression Regulation
  • ZAP70
  • Somatic Hypermutation, Immunoglobulin
  • Messenger RNA
  • NOTCH1
  • B-Lymphocytes
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (81)

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 T10, ADPRC 1 -CD38 and Chronic Lymphocytic Leukemia
318
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
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 -IGH and Chronic Lymphocytic Leukemia
156
CD19 16p11.2 B4, CVID3 -CD19 and Chronic Lymphocytic Leukemia
148
ATM 11q22.3 AT1, ATA, ATC, ATD, ATE, ATDC, TEL1, TELO1 -ATM and Chronic Lymphocytic Leukemia
79
NOTCH1 9q34.3 hN1, AOS5, TAN1, AOVD1 -NOTCH1 and Chronic Lymphocytic Leukemia
75
SF3B1 2q33.1 MDS, PRP10, Hsh155, PRPF10, SAP155, SF3b155 -SF3B1 and Chronic Lymphocytic Leukemia
52
CD40 20q12-q13.2 p50, Bp50, CDW40, TNFRSF5 -CD40 and Chronic Lymphocytic Leukemia
51
CD79B 17q23 B29, IGB, AGM6 -CD79B and Chronic Lymphocytic Leukemia
36
BIRC3 11q22.2 AIP1, API2, MIHC, CIAP2, HAIP1, HIAP1, MALT2, RNF49, c-IAP2 -BIRC3 and Chronic Lymphocytic Leukemia
36
CD22 19q13.1 SIGLEC2, SIGLEC-2 -CD22 and Chronic Lymphocytic Leukemia
25
TCL1A 14q32.1 TCL1 -TCL1A and Chronic Lymphocytic Leukemia
25
CD79A 19q13.2 IGA, MB-1 -CD79A and Chronic Lymphocytic Leukemia
20
SYK 9q22 p72-Syk -SYK and Chronic Lymphocytic Leukemia
20
AICDA 12p13 AID, ARP2, CDA2, HIGM2, HEL-S-284 -AICDA and Chronic Lymphocytic Leukemia
18
MCL1 1q21 TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1/EAT -MCL1 and Chronic Lymphocytic Leukemia
17
BCL3 19q13.32 BCL4, D19S37 -BCL3 and Chronic Lymphocytic Leukemia
17
IGL 22q11.2 IGL@, IGLC6 -IGL and Chronic Lymphocytic Leukemia
16
DLEU2 13q14.3 1B4, DLB2, LEU2, BCMSUN, RFP2OS, MIR15AHG, TRIM13OS, LINC00022, NCRNA00022 -DLEU2 and Chronic Lymphocytic Leukemia
15
CD80 3q13.3-q21 B7, BB1, B7-1, B7.1, LAB7, CD28LG, CD28LG1 -CD80 and Chronic Lymphocytic Leukemia
15
CD52 1p36 CDW52 -CD52 and Chronic Lymphocytic Leukemia
15
ITGA4 2q31.3 IA4, CD49D -ITGA4 and Chronic Lymphocytic Leukemia
15
ITGAX 16p11.2 CD11C, SLEB6 -ITGAX and Chronic Lymphocytic Leukemia
14
P2RX7 12q24 P2X7 -P2RX7 and Chronic Lymphocytic Leukemia
13
PMAIP1 18q21.32 APR, NOXA -PMAIP1 and Chronic Lymphocytic Leukemia
13
LYN 8q13 JTK8, p53Lyn, p56Lyn -LYN and Chronic Lymphocytic Leukemia
13
MYD88 3p22 MYD88D -MYD88 and Chronic Lymphocytic Leukemia
13
TNFRSF17 16p13.1 BCM, BCMA, CD269, TNFRSF13A -TNFRSF17 and Chronic Lymphocytic Leukemia
12
CD27 12p13 T14, S152, Tp55, TNFRSF7, S152. LPFS2 -CD27 and Chronic Lymphocytic Leukemia
11
DAPK1 9q21.33 DAPK -DAPK1 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-p23 MUM1, LSIRF, SHEP8, NF-EM5 -IRF4 and Chronic Lymphocytic Leukemia
10
BBC3 19q13.3-q13.4 JFY1, PUMA, JFY-1 -BBC3 and Chronic Lymphocytic Leukemia
10
PRAME 22q11.22 MAPE, OIP4, CT130, OIP-4 -PRAME and Chronic Lymphocytic Leukemia
9
TLR9 3p21.3 CD289 -TLR9 and Chronic Lymphocytic Leukemia
9
CCR7 17q12-q21.2 BLR2, EBI1, CCR-7, CD197, CDw197, CMKBR7, CC-CKR-7 -CCR7 and Chronic Lymphocytic Leukemia
8
LEF1 4q23-q25 LEF-1, TCF10, TCF7L3, TCF1ALPHA -LEF1 and Chronic Lymphocytic Leukemia
8
CD86 3q21 B70, B7-2, B7.2, LAB72, CD28LG2 -CD86 and Chronic Lymphocytic Leukemia
8
IL2 4q26-q27 IL-2, TCGF, lymphokine -IL2 and Chronic Lymphocytic Leukemia
8
DAPK2 15q22.31 DRP1, DRP-1 -DAPK2 and Chronic Lymphocytic Leukemia
8
TNFSF13B 13q32-q34 DTL, BAFF, BLYS, CD257, TALL1, THANK, ZTNF4, TALL-1, TNFSF20 -TNFSF13B and Chronic Lymphocytic Leukemia
7
CD69 12p13 AIM, EA1, MLR-3, CLEC2C, GP32/28, BL-AC/P26 -CD69 and Chronic Lymphocytic Leukemia
7
ROR1 1p31.3 NTRKR1, dJ537F10.1 -ROR1 and Chronic Lymphocytic Leukemia
7
POT1 7q31.33 CMM10, HPOT1 -POT1 and Chronic Lymphocytic Leukemia
6
ITGB2 21q22.3 LAD, CD18, MF17, MFI7, LCAMB, LFA-1, MAC-1 -ITGB2 and Chronic Lymphocytic Leukemia
6
CD200 3q13.2 MRC, MOX1, MOX2, OX-2 -CD200 and Chronic Lymphocytic Leukemia
5
CD74 5q32 II, DHLAG, HLADG, Ia-GAMMA -CD74 and Chronic Lymphocytic Leukemia
5
ADAM29 4q34 CT73, svph1 -ADAM29 and Chronic Lymphocytic Leukemia
5
CXCR5 11q23.3 BLR1, CD185, MDR15 -CXCR5 and Chronic Lymphocytic Leukemia
5
IL21 4q26-q27 Za11, IL-21, CVID11 -IL21 and Chronic Lymphocytic Leukemia
5
CD1D 1q23.1 R3, CD1A -CD1D and Chronic Lymphocytic Leukemia
5
CDR2 16p12.3 Yo, CDR62 -CDR2 and Chronic Lymphocytic Leukemia
5
RHOH 4p13 TTF, ARHH -RHOH and Chronic Lymphocytic Leukemia
4
XPO1 2p15 emb, CRM1, exp1 -XPO1 and Chronic Lymphocytic Leukemia
4
ITGAL 16p11.2 CD11A, LFA-1, LFA1A -ITGAL and Chronic Lymphocytic Leukemia
4
PIK3CD 1p36.2 APDS, PI3K, IMD14, p110D, P110DELTA -PIK3CD and Chronic Lymphocytic Leukemia
4
CD81 11p15.5 S5.7, CVID6, TAPA1, TSPAN28 -CD81 and Chronic Lymphocytic Leukemia
4
CMBL 5p15.2 JS-1 -CMBL and Chronic Lymphocytic Leukemia
4
TNFSF13 17p13.1 APRIL, CD256, TALL2, ZTNF2, TALL-2, TRDL-1, UNQ383/PRO715 -TNFSF13 and Chronic Lymphocytic Leukemia
4
BOLL 2q33 BOULE -BOLL and Chronic Lymphocytic Leukemia
3
LAMP1 13q34 LAMPA, CD107a, LGP120 -LAMP1 and Chronic Lymphocytic Leukemia
3
FBXW7 4q31.3 AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 -FBXW7 mutations in CLL
3
CRY1 12q23-q24.1 PHLL1 -CRY1 and Chronic Lymphocytic Leukemia
3
CCL17 16q13 TARC, ABCD-2, SCYA17, A-152E5.3 -CCL17 and Chronic Lymphocytic Leukemia
3
ARL11 13q14.2 ARLTS1 -ARL11 and Chronic Lymphocytic Leukemia
3
BCL11B 14q32.2 ATL1, RIT1, CTIP2, CTIP-2, ZNF856B, ATL1-beta, ATL1-alpha, ATL1-delta, ATL1-gamma, hRIT1-alpha -BCL11B and Chronic Lymphocytic Leukemia
3
IL16 15q26.3 LCF, NIL16, PRIL16, prIL-16 -IL16 and Chronic Lymphocytic Leukemia
3
CCL19 9p13 ELC, CKb11, MIP3B, MIP-3b, SCYA19 -CCL19 and Chronic Lymphocytic Leukemia
3
PAPPA 9q33.2 PAPA, DIPLA1, PAPP-A, PAPPA1, ASBABP2, IGFBP-4ase -PAPPA and Chronic Lymphocytic Leukemia
3
MIR34A 1p36.22 mir-34, MIRN34A, mir-34a, miRNA34A -MIR34A and Chronic Lymphocytic Leukemia
3
TRIM13 13q14 CAR, LEU5, RFP2, DLEU5, RNF77 -TRIM13 and Chronic Lymphocytic Leukemia
2
POLI 18q21.1 RAD30B, RAD3OB -POLI and Chronic Lymphocytic Leukemia
2
LTB 6p21.3 p33, TNFC, TNFSF3 -LTB and Chronic Lymphocytic Leukemia
1
MIR125A 19q13.41 MIRN125A, miRNA125A -MIR125A and Chronic Lymphocytic Leukemia
1
MS4A1 11q12.2 B1, S7, Bp35, CD20, CVID5, MS4A2, LEU-16 -MS4A1 and Chronic Lymphocytic Leukemia
1
ETV3 1q21-q23 PE1, METS, PE-1, bA110J1.4 -ETV3 and Chronic Lymphocytic Leukemia
1
TCL6 14q32.1 TNG1, TNG2 -TCL6 and Chronic Lymphocytic Leukemia
1
MYBL1 8q13.1 AMYB, A-MYB -MYBL1 and Chronic Lymphocytic Leukemia
1
SLAMF1 1q23.3 SLAM, CD150, CDw150 -SLAMF1 and Chronic Lymphocytic Leukemia
1
ROR2 9q22 BDB, BDB1, NTRKR2 -ROR2 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

Campregher PV, Petroni RC, Muto NH, et al.
A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia.
Biomed Res Int. 2016; 2016:4247908 [PubMed] Free Access to Full Article Related Publications
Aims. To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of NOTCH1 in order to evaluate patients with chronic lymphocytic leukemia (CLL). Methods. We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of NOTCH1. Results. We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of NOTCH1 mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. NOTCH1 mutations were detected in 43.7% of the patients with trisomy 12. Conclusions. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect NOTCH1 PEST domain insertions and deletions.

Khan AS, Hojjat-Farsangi M, Daneshmanesh AH, et al.
Dishevelled proteins are significantly upregulated in chronic lymphocytic leukaemia.
Tumour Biol. 2016; 37(9):11947-11957 [PubMed] Related Publications
Dishevelled (DVL) proteins are components of the Wnt signalling pathways, and increased expression is associated with various malignancies. Information on DVLs in chronic lymphatic leukaemia (CLL) is limited. The aim of the present study was to investigate the role of DVLs in CLL cells and association with Wnt pathways downstream of ROR1. DVL1, 2 and 3 were exclusively expressed in CLL cells as compared to normal peripheral blood mononuclear cells (PBMCs). The expression of DVL1 and DVL3 proteins was significantly more pronounced in progressive than in non-progressive disease (p < 0.01), whereas the level of DVL2 was significantly higher in non-progressive as compared to progressive disease (p < 0.001). Treatment of CLL cells with anti-ROR1 specific monoclonal antibodies induced dephosphorylation of ROR1 as well as of tyrosine and serine residues of both DVL2 and DVL3. However, gene silencing of DVLs in the CLL cell line (EHEB) did not induce detectable apoptosis. Non-progressive CLL patients had a different protein activity pattern with regard to Wnt signalling pathway proteins as GSK-3β, β-catenin and AKT as compared to progressive disease. The DVL2 protein may play a role in the activation of signalling pathways in CLL during early stages of the disease, while DVL1 and 3 may have a role in later phases of the leukaemia.

Minervini CF, Cumbo C, Orsini P, et al.
TP53 gene mutation analysis in chronic lymphocytic leukemia by nanopore MinION sequencing.
Diagn Pathol. 2016; 11(1):96 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The assessment of TP53 mutational status is becoming a routine clinical practice for chronic lymphocytic leukemia patients (CLL). A broad spectrum of molecular techniques has been employed so far, including both direct Sanger sequencing and next generation sequencing. Oxford Nanopore Technologies recently released the MinION an USB-interfaced sequencer. In this paper we report our experience, with the MinION technology for the detection of the TP53 gene mutation in CLL patients. Twelve CLL patients at diagnosis were included in this study. All except one patient showed the TP53 gene deletion in Fluorescence in situ hybridization experiments. Patients were investigated for TP53 mutation by Sanger and by MinION sequencing. Analysis by Sanger was performed according with the IARC protocol. Analysis by MinION was performed adopting a strategy based on long template PCR, read error correction, and post variant calling filtering.
RESULTS: Due to the high error rate of nanopore technology, sequence data were both used directly and before correction with two different in silico methods: ALEC and nanocorrect. A mean error rate of 15 % was detected before correction that was reduced to 4-5 % after correction. Analysis by Sanger sequencing was able to detect four patients mutated for TP53. MinION analysis detected one more mutated patient previously not detected from Sanger.
CONCLUSION: In our hands, the Nanopore technology shows correlation with Sanger sequencing but more sensitive, manageable and less expensive, and therefore has proven to be a useful tool for TP53 gene mutation detection.

González-Gascón Y Marín I, Martín AÁ, Hernández-Sanchez M, et al.
Hyperdiploidy as a rare event that accompanies poor prognosis markers in CLL.
Eur J Haematol. 2017; 98(2):142-148 [PubMed] Related Publications
The presence of chromosomal gains other than trisomy 12 in chronic lymphocytic leukaemia (CLL) is unusual. However, some patients may show gains on several chromosomes simultaneously suggesting a hyperdiploid karyotype.
OBJECTIVE: The objective of this study was to analyse by FISH the frequency and prognostic impact of hyperdiploidy in CLL.
METHOD: A review of 1359 consecutive cases diagnosed with CLL referred for FISH analysis to a unique institution was carried out. Hyperdiploidy was considered when a gain of at least three of the five FISH probes used was observed.
RESULTS: Seven cases (0.51%) with hyperdiploidy were found, confirming that it is a rare event in this disease. Although most patients presented with early Binet stages at diagnosis, six of seven (86%) shortly progressed. The median of time to the first therapy (TTFT) and overall survival (OS) for the patients with hyperdiploidy were short (1.4 months and 20 months, respectively). Moreover, comparing them with a control group of patients (non-hyperdiploid) with completed follow-up data, TTFT and OS of the patients with hyperdiploidy were significantly shorter than the control group.
CONCLUSION: The presence of hyperdiploidy is uncommon and probably associated with poor prognostic markers in CLL.

Schmidt-Wolf IG, Plass C, Byrd JC, et al.
Assessment of Promoter Methylation Identifies PTCH as a Putative Tumor-suppressor Gene in Human CLL.
Anticancer Res. 2016; 36(9):4515-9 [PubMed] Related Publications
BACKGROUND: Chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of neoplastic lymphocytes, indicating disruption of apoptosis.
PATIENTS AND METHODS: Differential methylation hybridization analysis was performed to identify novel target genes silenced by CpG island methylation in patients with CLL.
RESULTS: Patched (PTCH), a tumor-suppressor gene, was found to be frequently methylated in CLL samples compared to samples derived from healthy individuals. De novo methylation of a CpG island region located upstream of PTCH exon 1 was confirmed by pyrosequencing in 17/37 (46%) of peripheral blood mononuclear cells of patients with CLL, but in none isolated from seven healthy individuals. No association was found between PTCH hypermethylation and currently used prognostic CLL factors.
CONCLUSION: Our investigation suggests that epigenetic silencing of PTCH is a mechanism contributing to CLL tumorigenesis.

Holmes PJ, Peiper SC, Uppal GK, et al.
Efficacy of DSP30-IL2/TPA for detection of cytogenetic abnormalities in chronic lymphocytic leukaemia/small lymphocytic lymphoma.
Int J Lab Hematol. 2016; 38(5):483-9 [PubMed] Related Publications
INTRODUCTION: Chronic lymphocytic leukaemia (CLL) is the most prevalent leukaemia in the Western Hemisphere. Cytogenetic abnormalities in CLL are used for diagnosis, prognosis and treatment. However, detecting these is difficult because mature B cells do not readily divide in culture. Here, we present data on two mitogen cocktails: CpG-oligonucleotide DSP30/Interleukin-2 (IL-2) and DSP30/IL-2 in combination with 12-O-tetradecanoylphorbol-13-acetate (TPA).
METHODS: We analysed 165 cases of CLL with FISH and cytogenetics from January 2011 to June 2013. In 2011, three cultures were set-up: unstimulated, DSP30/IL-2-stimulated and TPA-stimulated. In 2012-2013, two cultures were set-up: unstimulated and stimulated with TPA/DSP30/IL-2.
RESULTS: In 2011, FISH had a detection rate of 91% and cytogenetics using DSP30/IL2 had a detection rate of 91% (n = 22). In 2012-2013, FISH had a detection rate of 79% and cytogenetics using TPA/DSP30/IL-2 had a detection rate of 98% (n = 40). The percentage of cases with normal FISH but abnormal cytogenetics increased from 9% in 2011 to 21% in 2012-2013. The TPA/DSP30/IL-2 cultures in 2012-2013 detected more novel abnormalities (n = 5) as compared to DSP30/IL-2 alone (n = 3).
CONCLUSIONS: TPA/DSP30/IL2 was as good as or better than DSP30/IL2 alone. TPA/DSP30/IL-2 offers a high detection rate for CLL abnormalities with a single stimulated culture and may increase detection of clinically significant abnormalities.

Dai Z, Feng C, Zhang W, et al.
Lack of association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms and lymphoid malignancy risk: evidence from a meta-analysis.
Ann Hematol. 2016; 95(10):1685-94 [PubMed] Related Publications
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms have been associated with susceptibility to lymphoid malignancies. However, results from the published single studies are inconsistent. Therefore, the present meta-analysis was conducted to get a more accurate estimation of the relationship between CTLA-4 gene polymorphisms and the lymphoid malignancy risk. We identified nine independent studies accounting for 3090 subjects up to January 30, 2016. Summary odds ratios (OR) and 95 % confidence intervals (CI) were used to evaluate the risk of lymphoid malignancies. Overall, no significant association was found between +49A/G (rs231775), -318C/T (rs5742909), and +6230A/G (rs3087243) CTLA-4 gene polymorphisms and lymphoid malignancies. Furthermore, ethnicity (Asian and Caucasian) and histopathology subgroup analyses (non-Hodgkin's lymphoma) also failed to detect an association between the studied polymorphisms and lymphoid malignancy risk. Our study shows that common CTLA-4 gene polymorphisms may not contribute to lymphoid malignancy susceptibility based on the current evidence.

Jasek M, Bojarska-Junak A, Wagner M, et al.
Association of variants in BAFF (rs9514828 and rs1041569) and BAFF-R (rs61756766) genes with the risk of chronic lymphocytic leukemia.
Tumour Biol. 2016; 37(10):13617-13626 [PubMed] Free Access to Full Article Related Publications
The B-cell activator factor (BAFF)/BAFF receptor (BAFF-R) axis seems to play an important role in the development and progression of chronic lymphocytic leukemia (CLL). Here, we investigated the association of eight single nucleotide polymorphisms (SNPs) in the BAFF (TNFSF13B) and BAFF-R (TNFRSF13C) genes with risk of sporadic CLL in a group of 439 CLL patients and 477 controls. We also examined the correlation between selected SNPs and CLL clinical parameters as well as BAFF plasma levels and intracellular BAFF expression. Our results point to a possible association between the rs9514828 (CT vs. CC + TT; OR = 0.74; CI 95 % = 0.57; 0.97; p = 0.022) and rs1041569 (AT vs. AA + TT; OR = 0.72; CI 95 % = 0.54; 0.95; p = 0.021) of BAFF gene and rs61756766 (CC vs. CT; OR = 2.03; CI 95 % = 1.03; 3.99; p = 0.03) of BAFF-R gene and CLL risk. Additionally, we observed that homozygotes rs1041569 AA and TT had a slightly higher risk (HR = 1.12) for the need of treatment in comparison to AT heterozygotes. In conclusion, our results indicate that SNPs in BAFF and BAFF-R genes may be considered as potential CLL risk factors.

Scarfò L, Ferreri AJ, Ghia P
Chronic lymphocytic leukaemia.
Crit Rev Oncol Hematol. 2016; 104:169-82 [PubMed] Related Publications
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among the adults in the Western World. CLL (and the corresponding nodal entity small lymphocytic lymphoma, SLL) is classified as a lymphoproliferative disorder characterised by the relentless accumulation of mature B-lymphocytes showing a peculiar immunophenotype in the peripheral blood, bone marrow, lymph nodes and spleen. CLL clinical course is very heterogeneous: the majority of patients follow an indolent clinical course with no or delayed treatment need and with a prolonged survival, while others experience aggressive disease requiring early treatment followed by frequent relapses. In the last decade, the improved understanding of CLL pathogenesis shed light on premalignant conditions (i.e., monoclonal B-cell lymphocytosis, MBL), defined new prognostic and predictive markers, improving patient stratification, but also broadened the therapeutic armamentarium with novel agents, targeting fundamental signaling pathways.

Lin X, Chen J, Huang H
Immunostimulation by cytosine-phosphate-guanine oligodeoxynucleotides in combination with IL-2 can improve the success rate of karyotype analysis in chronic lymphocytic leukaemia.
Br J Biomed Sci. 2016; 73(3):110-114 [PubMed] Related Publications
PURPOSE: To assess whether immunostimulatory cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODN) combined with interleukin-2 (IL-2) improves the number of mitotic metaphases and the detection rate of chromosomal abnormalities in chronic lymphocytic leukaemia (CLL).
MATERIALS AND METHODS: Bone marrow specimens were collected from 36 patients with CLL. CLL cells were cultured with CpG-ODN type DSP30 plus IL-2 for 72 h, following which R-banding analysis was conducted. Conventional culture without the immunostimulant served as the control group. The incidence of genetic abnormalities was measured by fluorescence in situ hybridisation (FISH) using a panel of five specific probes: D13S25 (13q14.3), RB1 (13q14), P53 (17p13), ATM (11q22.3) and CSP12 (trisomy 12, +12).
RESULTS: In the control group, chromosome analysis achieved a success rate of only 22.2, and 11.1% of abnormal karyotypes were detected. After immunostimulation with DSP30 plus IL-2, chromosome analysis achieved a success rate of up to 91.6, and 41.6% of abnormal karyotypes were detected. FISH analysis detected 77.7% of abnormalities. FISH combined with CpG-ODN DSP30 plus IL-2 improved the detection rate of chromosomal abnormalities in CLL to 83.3%.
CONCLUSION: CpG-ODN DSP30 combined with IL-2 is effective in improving the detection rate of chromosomal abnormalities in CLL cells. This combination with FISH analysis is conducive to increasing the detection rate of genetic abnormalities in CLL.

Haney SL, Upchurch GM, Opavska J, et al.
Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a.
Cell Rep. 2016; 15(6):1190-201 [PubMed] Free Access to Full Article Related Publications
DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65% of Dnmt3a(+/-) mice develop a CLL-like disease, and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a(+/-) and Dnmt3a(Δ/Δ) CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene expression analysis identified 26 hypomethylated and overexpressed genes common to both Dnmt3a(+/-) and Dnmt3a(Δ/Δ) CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.

Pekarsky Y, Balatti V, Palamarchuk A, et al.
Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer.
Proc Natl Acad Sci U S A. 2016; 113(18):5071-6 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and transgenic mouse studies indicate that activation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease. While studying the regulation of TCL1 expression, we identified the microRNA cluster miR-4521/3676 and discovered that these two microRNAs are associated with tRNA sequences and that this region can produce two small RNAs, members of a recently identified class of small noncoding RNAs, tRNA-derived small RNAs (tsRNAs). We further proved that miR-3676 and miR-4521 are tsRNAs using Northern blot analysis. We found that, like ts-3676, ts-4521 is down-regulated and mutated in CLL. Analysis of lung cancer samples revealed that both ts-3676 and ts-4521 are down-regulated and mutated in patient tumor samples. Because tsRNAs are similar in nature to piRNAs [P-element-induced wimpy testis (Piwi)-interacting small RNAs], we investigated whether ts-3676 and ts-4521 can interact with Piwi proteins and found these two tsRNAs in complexes containing Piwi-like protein 2 (PIWIL2). To determine whether other tsRNAs are involved in cancer, we generated a custom microarray chip containing 120 tsRNAs 16 bp or more in size. Microarray hybridization experiments revealed tsRNA signatures in CLL and lung cancer, indicating that, like microRNAs, tsRNAs may have an oncogenic and/or tumor-suppressor function in hematopoietic malignancies and solid tumors. Thus, our results show that tsRNAs are dysregulated in human cancer.

Rossi D, Gaidano G
Richter syndrome: pathogenesis and management.
Semin Oncol. 2016; 43(2):311-9 [PubMed] Related Publications
Richter syndrome (RS) is the development of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL). The incidence rate RS is ~0.5% per year of observation. Two biomarkers (NOTCH1 mutations and subset 8 configuration of the B-cell receptor) may help identifying CLL patients at risk of RS to be considered for close monitoring and a careful biopsy policy. In the presence of clinical features suspicious of RS, diagnosis of transformation and choice of the site of biopsy may take advantage of fluorine 18 fluorodeoxyglucose ((18)FDG) positron emission tomography (PET)/computed tomography (CT). Molecular lesions of regulators of tumor suppression (TP53), cell cycle (CDKN2A), and cell proliferation (NOTCH1, MYC) overall account for ~90% of RS and may be responsible for the aggressive clinical phenotype observed in this disease because of the combined effect of chemoresistance and rapid disease kinetics. The prognosis of RS is generally highly unfavorable. However, the pattern of survival is not homogeneous and the most important prognostic factor is the clonal relationship between the CLL and the aggressive lymphoma clones. Rituximab-containing polychemotherapy represents the backbone for induction treatment in RS. Younger patients who respond to induction therapy should be offered stem cell transplant (SCT) to prolong survival.

Amin NA, Malek SN
Gene mutations in chronic lymphocytic leukemia.
Semin Oncol. 2016; 43(2):215-21 [PubMed] Related Publications
The recent discovery of genes mutated in chronic lymphocytic leukemia (CLL) has stimulated new research into the role of these genes in CLL pathogenesis. CLL cases carry approximately 5-20 mutated genes per exome, a lower number than detected in many human tumors. Of the recurrently mutated genes in CLL, all are mutated in 10% or less of patients when assayed in unselected CLL cohorts at diagnosis. Mutations in TP53 are of major clinical relevance, are often associated with del17p and gain in frequency over time. TP53 mutated and associated del17p states substantially lower response rates, remission duration, and survival in CLL. Mutations in NOTCH1 and SF3B1 are recurrent, often associated with progressive CLL that is also IgVH unmutated and ZAP70-positive and are under investigation as targets for novel therapies and as factors influencing CLL outcome. There are an estimated 20-50 additional mutated genes with frequencies of 1%-5% in CLL; more work is needed to identify these and to study their significance. Finally, of the major biological aberration categories influencing CLL as a disease, gene mutations will need to be placed into context with regard to their ultimate role and importance. Such calibrated appreciation necessitates studies incorporating multiple CLL driver aberrations into biological and clinical analyses.

Van Roosbroeck K, Calin GA
MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies?
Semin Oncol. 2016; 43(2):209-14 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease and has a highly variable clinical course with survival ranging from a couple of months to several decades. MicroRNAs (miRNAs), small non-coding RNAs that regulate transcription and translation of genes, have been found to be involved in CLL initiation, progression, and resistance to therapy. In addition, they can be used as prognostic biomarkers and as targets for novel therapies. In this review, we describe the association between miRNAs and the cytogenetic aberrations commonly found in CLL, as well as with other prognostic factors. We describe the presence of miRNAs as extracellular entities in the plasma and serum of CLL patients and discuss their role in resistance to therapy. Finally, we will explore the potential of targeted miRNA therapy for the treatment of CLL, with a special emphasis on MRX34, the first miRNA mimic that is currently being evaluated for clinical use.

Rossi D, Gaidano G
The clinical implications of gene mutations in chronic lymphocytic leukaemia.
Br J Cancer. 2016; 114(8):849-54 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs.

Johnson N, De Ieso P, Migliorini G, et al.
Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.
Cancer Res. 2016; 76(6):1485-93 [PubMed] Free Access to Full Article Related Publications
CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.

Kasar S, Underbayev C, Hassan M, et al.
Alterations in the mir-15a/16-1 Loci Impairs Its Processing and Augments B-1 Expansion in De Novo Mouse Model of Chronic Lymphocytic Leukemia (CLL).
PLoS One. 2016; 11(3):e0149331 [PubMed] Free Access to Full Article Related Publications
New Zealand Black (NZB) mice, a de novo model of CLL, share multiple characteristics with CLL patients, including decreased expression of miR-15a/16-1. We previously discovered a point mutation and deletion in the 3' flanking region of mir-16-1 of NZB and a similar mutation has been found in a small number of CLL patients. However, it was unknown whether the mutation is the cause for the reduced miR-15a/16-1 expression and CLL development. Using PCR and in vitro microRNA processing assays, we found that the NZB sequence alterations in the mir-15a/16-1 loci result in deficient processing of the precursor forms of miR-15a/16-1, in particular, we observe impaired conversion of pri-miR-15a/16-1 to pre-miR-15a/16-1. The in vitro data was further supported by derivation of congenic strains with replaced mir-15a/16-1 loci at one or both alleles: NZB congenic mice (NmiR+/-) and DBA congenic mice (DmiR-/-). The level of miR-15a/16-1 reflected the configuration of the mir-15a/16-1 loci with DBA congenic mice (DmiR-/-) showing reduced miR-15a levels compared to homozygous wild-type allele, while the NZB congenic mice (NmiR+/-) showed an increase in miR-15a levels relative to homozygous mutant allele. Similar to Monoclonal B-cell Lymphocytosis (MBL), the precursor stage of the human disease, an overall expansion of the B-1 population was observed in DBA congenic mice (DmiR-/-) relative to wild-type (DmiR+/+). These studies support our hypothesis that the mutations in the mir-15a/16-1 loci are responsible for decreased expression of this regulatory microRNA leading to B-1 expansion and CLL development.

Koczkodaj D, Popek S, Zmorzyński S, et al.
Detection of chromosomal changes in chronic lymphocytic leukemia using classical cytogenetic methods and FISH: application of rich mitogen mixtures for lymphocyte cultures.
J Investig Med. 2016; 64(4):894-8 [PubMed] Related Publications
One of the research methods of prognostic value in chronic lymphocytic leukemia (CLL) is cytogenetic analysis. This method requires the presence of appropriate B-cell mitogens in cultures in order to obtain a high mitotic index. The aim of our research was to determine the most effective methods of in vitro B-cell stimulation to maximize the number of metaphases from peripheral blood cells of patients with CLL for classical cytogenetic examination, and then to correlate the results with those obtained using fluorescence in situ hybridization (FISH). The study group involved 50 consecutive patients with CLL. Cell cultures were maintained with the basic composition of culture medium and addition of respective stimulators. We used the following stimulators: Pokeweed Mitogen (PWM), 12-O-tetradecanoylphorbol 13-acetate (TPA), ionophore, lipopolysaccharide (LPS), and CpG-oligonucleotide DSP30. We received the highest mitotic index when using the mixture of PWM+TPA+I+DSP30. With classical cytogenetic tests using banding techniques, numerical and structural aberrations of chromosomes were detected in 46 patients, and no change was found in only four patients. Test results clearly confirmed the legitimacy of using cell cultures enriched with the mixture of cell stimulators and combining classical cytogenetic techniques with the FISH technique in later patient diagnosing.

Berndt SI, Camp NJ, Skibola CF, et al.
Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.
Nat Commun. 2016; 7:10933 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

Ristić S, Radojković M, Kostić T, et al.
JAK2V617F Mutation in a Patient with B-cell Chronic Lymphocytic Leukemia and Prefibrotic Primary Myelofibrosis.
Srp Arh Celok Lek. 2015 Nov-Dec; 143(11-12):739-43 [PubMed] Related Publications
INTRODUCTION: Secondary malignancies, particularly solid tumors, are common in patients with chronic lymphocytic leukemia (CLL), but association of myeloproliferative neoplasms and chronic lymphocytic leukemia in the same patient is very rare.
CASE OUTLINE: We report of a 67-year-old man with B-cell chronic lymphoid leukemia (B-CLL) who developed primary myelofibrosis (PMF) nine years after initial diagnosis. Patient received alkylation agents and purine analogue, which can be a predisposing factor for the development of myeloproliferative neoplasms. JAK2V617F mutation was not present initially at the time of CLL diagnosis, but was found after nine years when PMF occurred, which indicates that B-CLL and PMF represent two separate clonal origin neoplasms.
CONCLUSION: Pathogenic mechanisms for the development of myeloproliferative and lymphoproliferative neoplasms in the same patient are unknown. Further research is needed to determine whether these malignancies originate from two different cell clones or arise from the same pluripotent hematopoietic stem cell.

Fabbri G, Dalla-Favera R
The molecular pathogenesis of chronic lymphocytic leukaemia.
Nat Rev Cancer. 2016; 16(3):145-62 [PubMed] Related Publications
Recent investigations have provided an increasingly complete picture of the genetic landscape of chronic lymphocytic leukaemia (CLL). These analyses revealed that the CLL genome displays a high degree of heterogeneity between patients and within the same patient. In addition, they highlighted molecular mechanisms and functionally relevant biological programmes that may be important for the pathogenesis and therapeutic targeting of this disease. This Review focuses on recent insights into the understanding of CLL biology, with emphasis on the role of genetic lesions in the initiation and clinical progression of CLL. We also consider the translation of these findings into the development of risk-adapted and targeted therapeutic approaches.

Dong L, Bi KH, Huang N, Chen CY
Biological analysis of chronic lymphocytic leukemia: integration of mRNA and microRNA expression profiles.
Genet Mol Res. 2016; 15(1) [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a disease that involves progressive accumulation of nonfunctioning lymphocytes and has a low cure rate. There is an urgent requirement to determine the molecular mechanism underlying this disease in order to improve the early diagnosis and treatment of CLL. In this study, genes differentially expressed between CLL samples and age-matched controls were identified using microRNA (miRNA) and mRNA expression profiles. Differentially expressed (DE) miRNA targets were predicted by combining five algorithms. Common genes were obtained on overlapping the DE mRNA and DE miRNA targets. Then, network and module analyses were performed. A total of 239 miRNA targets were predicted and 357 DE mRNAs were obtained. On intersecting miRNA targets and DE mRNAs, 33 common genes were obtained. The protein-protein interaction network and module analysis identified several crucial genes and modules that might be associated with the development of CLL. These DE mRNAs were significantly enriched in the hematopoietic cell lineage (P = 2.58E-4), mitogen-activated protein kinase signaling pathway (P = 0.0025), and leukocyte transendothelial migration pathway (P = 0.0026). Thus, we conducted biological analysis on integration of DE mRNAs and DE miRNAs in CLL, determined gene expression patterns, and screened out several important genes that might be related to CLL.

Langerbeins P, Groß-Ophoff-Müller C, Herling CD
Risk-Adapted Therapy in Early-Stage Chronic Lymphocytic Leukemia.
Oncol Res Treat. 2016; 39(1-2):18-24 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and usually affects the elderly patient. More than 50% of CLL cases are diagnosed at an early disease stage, often as an incidental lymphocytosis found in a routine blood screen. For about 40 years, the classifications according to Binet or Rai have been the hands-on staging systems to stratify patients in daily clinical practice. An increasing molecular understanding of the disease and the identification of strong prognostic markers, such as genetic lesions in TP53, have urged clinical scientists to create new scoring systems that improve prognostic risk assessment and treatment allocation. Until today, studies on early treatment interventions in asymptomatic patients using single chemo- or combined chemoimmunotherapy have failed to demonstrate a survival benefit. However, improved risk stratification tools integrating molecular disease features and the availability of new targeted drugs with attractive efficacy and limited toxicity might open new possibilities to re-investigate early treatment in well-defined clinical settings in the future.

Tausch E, Mertens D, Stilgenbauer S
Genomic Features: Impact on Pathogenesis and Treatment of Chronic Lymphocytic Leukemia.
Oncol Res Treat. 2016; 39(1-2):34-40 [PubMed] Related Publications
Genomic markers are among the strongest prognostic factors in chronic lymphocytic leukemia (CLL). Chromosomal aberrations, IGHV and TP53 mutation status are well-established and essential to discriminate between a more indolent course of disease and a high-risk CLL, which requires an alternative treatment regimen. In addition, a variety of gene mutations with unclear prognostic value have been identified: SF3B1, ATM, and BIRC3 may describe CLL with adverse outcome, whereas NOTCH1 is predictive for resistance against CD20 antibodies. Integration of novel drivers into a small set of key pathways forms the basis for future pathogenetic and therapeutic implications.

Van Dyke DL, Werner L, Rassenti LZ, et al.
The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience.
Br J Haematol. 2016; 173(1):105-13 [PubMed] Free Access to Full Article Related Publications
This study revisited the Dohner prognostic hierarchy in a cohort of 1585 well-documented patients with chronic lymphocytic leukaemia. The duration of both time to first treatment (TTFT) and overall survival (OS) were significantly longer than observed previously, and this is at least partly due to improved therapeutic options. Deletion 13q remains the most favourable prognostic group with median TTFT and OS from fluorescence in situ hybridization (FISH) testing of 72 months and >12 years, respectively. Deletion 11q had the poorest median TTFT (22 months) and 17p deletion the poorest median OS (5 years). The percentages of abnormal nuclei were significantly associated with differential TTFT for the trisomy 12, 13q and 17p deletion cohorts but not for the 11q deletion cohort. From the date of the first FISH study, patients with >85% 13q deletion nuclei had a notably shorter TTFT (24 months). Patients with ≤20% 17p deletion nuclei had longer median TTFT and OS from the date of the first FISH study (44 months and 11 years), and were more likely to be IGHV mutated.

Davis Z, Forconi F, Parker A, et al.
The outcome of Chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity.
Br J Haematol. 2016; 173(1):127-36 [PubMed] Related Publications
IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia (CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment (TTFT) among Stage A patients and in overall survival (OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial. Cox Regression analyses in the Stage A cohort revealed that a model which incorporated <97%, 97-98·99% and ≥99% identity as subgroups, was a better predictor of TTFT in CLL than using the 98% cut-off. Multivariate analysis selected the three mutational subgroups as independent predictors of TTFT in Stage A patients, and of OS in the diagnostic cohort. This study highlights that cases with 97% identity should not be considered to have the same prognosis as other cases with mutated IGHV genes defined as <98% identity to germline.

Parikh SA, Strati P, Tsang M, et al.
Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis.
Blood. 2016; 127(14):1752-60 [PubMed] Related Publications
Since the first description of the natural history of chronic lymphocytic leukemia (CLL) by David Galton in 1966, the considerable heterogeneity in the disease course has been well recognized. The Rai and Binet staging systems described ∼40 years ago have proven to be robust prognostic tools. Over the past 2 decades, several novel biological, genetic, and molecular markers have been shown to be useful adjuncts to the Rai and Binet staging systems. In this systematic review, we examined the role of immunoglobulin heavy-chain variable region gene (IGHV) mutation status and genetic abnormalities determined by interphase fluorescence in situ hybridization (FISH) in patients with newly diagnosed CLL. The cumulative evidence presented in this systematic review is sufficient to recommend that FISH and IGHV be performed as standard clinical tests for all patients with newly diagnosed CLL in those countries with the resources to do so. In addition to clinical stage, these parameters could represent the minimal standard initial prognostic evaluation for patients with CLL. This approach will allow the application of powerful, recently developed prognostic indices (all of which are dependent on IGHV and FISH results) to all patients with newly diagnosed CLL.

Paggetti J, Moussay E
BCR engagement in CLL: when translation goes wrong.
Blood. 2016; 127(4):378-80 [PubMed] Related Publications
In this issue of Blood, Yeomans et al identify MYC as an important target for translational regulation in chronic lymphocytic leukemia (CLL) cells after B-cell receptor (BCR) stimulation and show that current therapies suppress this induction.

Bresin A, D'Abundo L, Narducci MG, et al.
TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia.
Cell Death Dis. 2016; 7:e2071 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy with a mature phenotype. In spite of its relatively indolent nature, no radical cure is as yet available. CLL is not associated with either a unique cytogenetic or a molecular defect, which might have been a potential therapeutic target. Instead, several factors are involved in disease development, such as environmental signals which interact with genetic abnormalities to promote survival, proliferation and an immune surveillance escape. Among these, PI3-Kinase signal pathway alterations are nowadays considered to be clearly important. The TCL1 gene, an AKT co-activator, is the cause of a mature T-cell leukemia, as well as being highly expressed in all B-CLL. A TCL1 transgenic mouse which reproduces leukemia with a distinct immunophenotype and similar to the course of the human B-CLL was developed several years ago and is widely used by many groups. This is a review of the CLL biology arising from work of many independent investigators who have used TCL1 transgenic mouse model focusing on pathogenetic, microenviroment and therapeutic targets.

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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