CLL - Molecular Biology


Literature Analysis

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Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (76)

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'.

CD38 4p15 T10, ADPRC 1 -CD38 and Chronic Lymphocytic Leukemia
ZAP70 2q12 SRK, STD, TZK, STCD, ZAP-70 -ZAP70 and Chronic Lymphocytic Leukemia
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and Chronic Lymphocytic Leukemia
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 -IGH and Chronic Lymphocytic Leukemia
CD19 16p11.2 B4, CVID3 -CD19 and Chronic Lymphocytic Leukemia
NOTCH1 9q34.3 hN1, AOS5, TAN1, AOVD1 -NOTCH1 and Chronic Lymphocytic Leukemia
ATM 11q22-q23 AT1, ATA, ATC, ATD, ATE, ATDC, TEL1, TELO1 -ATM and Chronic Lymphocytic Leukemia
MS4A1 11q12 B1, S7, Bp35, CD20, CVID5, MS4A2, LEU-16 -MS4A1 and Chronic Lymphocytic Leukemia
SF3B1 2q33.1 MDS, PRP10, Hsh155, PRPF10, SAP155, SF3b155 -SF3B1 and Chronic Lymphocytic Leukemia
CD40 20q12-q13.2 p50, Bp50, CDW40, TNFRSF5 -CD40 and Chronic Lymphocytic Leukemia
CD79B 17q23 B29, IGB, AGM6 -CD79B and Chronic Lymphocytic Leukemia
TCL1A 14q32.1 TCL1 -TCL1A and Chronic Lymphocytic Leukemia
CD22 19q13.1 SIGLEC2, SIGLEC-2 -CD22 and Chronic Lymphocytic Leukemia
SYK 9q22 p72-Syk -SYK and Chronic Lymphocytic Leukemia
CD79A 19q13.2 IGA, MB-1 -CD79A and Chronic Lymphocytic Leukemia
AICDA 12p13 AID, ARP2, CDA2, HIGM2, HEL-S-284 -AICDA and Chronic Lymphocytic Leukemia
BCL3 19q13.1-q13.2 BCL4, D19S37 -BCL3 and Chronic Lymphocytic Leukemia
IGL 22q11.2 IGL@, IGLC6 -IGL and Chronic Lymphocytic Leukemia
CD80 3q13.3-q21 B7, BB1, B7-1, B7.1, LAB7, CD28LG, CD28LG1 -CD80 and Chronic Lymphocytic Leukemia
CD52 1p36 CDW52 -CD52 and Chronic Lymphocytic Leukemia
ITGA4 2q31.3 IA4, CD49D -ITGA4 and Chronic Lymphocytic Leukemia
BIRC3 11q22 AIP1, API2, MIHC, CIAP2, HAIP1, HIAP1, MALT2, RNF49, c-IAP2 -BIRC3 and Chronic Lymphocytic Leukemia
DLEU2 13q14.3 1B4, DLB2, LEU2, BCMSUN, RFP2OS, MIR15AHG, TRIM13OS, LINC00022, NCRNA00022 -DLEU2 and Chronic Lymphocytic Leukemia
MCL1 1q21 TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1/EAT -MCL1 and Chronic Lymphocytic Leukemia
PMAIP1 18q21.32 APR, NOXA -PMAIP1 and Chronic Lymphocytic Leukemia
ITGAX 16p11.2 CD11C, SLEB6 -ITGAX and Chronic Lymphocytic Leukemia
P2RX7 12q24 P2X7 -P2RX7 and Chronic Lymphocytic Leukemia
LYN 8q13 JTK8, p53Lyn, p56Lyn -LYN and Chronic Lymphocytic Leukemia
TNFRSF17 16p13.1 BCM, BCMA, CD269, TNFRSF13A -TNFRSF17 and Chronic Lymphocytic Leukemia
CD27 12p13 T14, S152, Tp55, TNFRSF7, S152. LPFS2 -CD27 and Chronic Lymphocytic Leukemia
DAPK1 9q21.33 DAPK -DAPK1 and Chronic Lymphocytic Leukemia
BCL11A 2p16.1 EVI9, CTIP1, ZNF856, HBFQTL5, BCL11A-L, BCL11A-S, BCL11a-M, BCL11A-XL -BCL11A and Chronic Lymphocytic Leukemia
BBC3 19q13.3-q13.4 JFY1, PUMA, JFY-1 -BBC3 and Chronic Lymphocytic Leukemia
MYD88 3p22 MYD88D -MYD88 and Chronic Lymphocytic Leukemia
PRAME 22q11.22 MAPE, OIP4, CT130, OIP-4 -PRAME and Chronic Lymphocytic Leukemia
TLR9 3p21.3 CD289 -TLR9 and Chronic Lymphocytic Leukemia
IRF4 6p25-p23 MUM1, LSIRF, SHEP8, NF-EM5 -IRF4 and Chronic Lymphocytic Leukemia
DAPK2 15q22.31 DRP1, DRP-1 -DAPK2 and Chronic Lymphocytic Leukemia
CCR7 17q12-q21.2 BLR2, EBI1, CCR-7, CD197, CDw197, CMKBR7, CC-CKR-7 -CCR7 and Chronic Lymphocytic Leukemia
LEF1 4q23-q25 LEF-1, TCF10, TCF7L3, TCF1ALPHA -LEF1 and Chronic Lymphocytic Leukemia
CD86 3q21 B70, B7-2, B7.2, LAB72, CD28LG2 -CD86 and Chronic Lymphocytic Leukemia
ROR1 1p31.3 NTRKR1, dJ537F10.1 -ROR1 and Chronic Lymphocytic Leukemia
CD69 12p13 AIM, EA1, MLR-3, CLEC2C, GP32/28, BL-AC/P26 -CD69 and Chronic Lymphocytic Leukemia
TNFSF13B 13q32-q34 DTL, BAFF, BLYS, CD257, TALL1, THANK, ZTNF4, TALL-1, TNFSF20 -TNFSF13B and Chronic Lymphocytic Leukemia
IL2 4q26-q27 IL-2, TCGF, lymphokine -IL2 and Chronic Lymphocytic Leukemia
POT1 7q31.33 CMM10, HPOT1 -POT1 and Chronic Lymphocytic Leukemia
ADAM29 4q34 CT73, svph1 -ADAM29 and Chronic Lymphocytic Leukemia
CXCR5 11q23.3 BLR1, CD185, MDR15 -CXCR5 and Chronic Lymphocytic Leukemia
IL21 4q26-q27 Za11, IL-21, CVID11 -IL21 and Chronic Lymphocytic Leukemia
CD1D 1q23.1 R3, CD1A -CD1D and Chronic Lymphocytic Leukemia
CDR2 16p12.3 Yo, CDR62 -CDR2 and Chronic Lymphocytic Leukemia
CD200 3q13.2 MRC, MOX1, MOX2, OX-2 -CD200 and Chronic Lymphocytic Leukemia
RHOH 4p13 TTF, ARHH -RHOH and Chronic Lymphocytic Leukemia
PIK3CD 1p36.2 APDS, PI3K, IMD14, p110D, P110DELTA -PIK3CD and Chronic Lymphocytic Leukemia
CMBL 5p15.2 JS-1 -CMBL and Chronic Lymphocytic Leukemia
TNFSF13 17p13.1 APRIL, CD256, TALL2, ZTNF2, TALL-2, TRDL-1, UNQ383/PRO715 -TNFSF13 and Chronic Lymphocytic Leukemia
XPO1 2p15 emb, CRM1, exp1 -XPO1 and Chronic Lymphocytic Leukemia
LAMP1 13q34 LAMPA, CD107a, LGP120 -LAMP1 and Chronic Lymphocytic Leukemia
FBXW7 4q31.3 AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 -FBXW7 mutations in CLL
CRY1 12q23-q24.1 PHLL1 -CRY1 and Chronic Lymphocytic Leukemia
ARL11 13q14.2 ARLTS1 -ARL11 and Chronic Lymphocytic Leukemia
CCL17 16q13 TARC, ABCD-2, SCYA17, A-152E5.3 -CCL17 and Chronic Lymphocytic Leukemia
IL16 15q26.3 LCF, NIL16, PRIL16, prIL-16 -IL16 and Chronic Lymphocytic Leukemia
CCL19 9p13 ELC, CKb11, MIP3B, MIP-3b, SCYA19 -CCL19 and Chronic Lymphocytic Leukemia
BCL11B 14q32.2 ATL1, RIT1, CTIP2, CTIP-2, ZNF856B, ATL1-beta, ATL1-alpha, ATL1-delta, ATL1-gamma, hRIT1-alpha -BCL11B and Chronic Lymphocytic Leukemia
MIR34A 1p36.22 mir-34, MIRN34A, miRNA34A -MIR34A and Chronic Lymphocytic Leukemia
PAPPA 9q33.2 PAPA, DIPLA1, PAPP-A, PAPPA1, ASBABP2, IGFBP-4ase -PAPPA and Chronic Lymphocytic Leukemia
BOLL 2q33 BOULE -BOLL and Chronic Lymphocytic Leukemia
TRIM13 13q14 CAR, LEU5, RFP2, DLEU5, RNF77 -TRIM13 and Chronic Lymphocytic Leukemia
LTB 6p21.3 p33, TNFC, TNFSF3 -LTB and Chronic Lymphocytic Leukemia
ETV3 1q21-q23 PE1, METS, PE-1, bA110J1.4 -ETV3 and Chronic Lymphocytic Leukemia
MIR125A 19q13.41 MIRN125A, miRNA125A -MIR125A and Chronic Lymphocytic Leukemia
TCL6 14q32.1 TNG1, TNG2 -TCL6 and Chronic Lymphocytic Leukemia
MYBL1 8q13.1 AMYB, A-MYB -MYBL1 and Chronic Lymphocytic Leukemia
SLAMF1 1q23.3 SLAM, CD150, CDw150 -SLAMF1 and Chronic Lymphocytic Leukemia
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

Yeh YY, Ozer HG, Lehman AM, et al.
Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling.
Blood. 2015; 125(21):3297-305 [PubMed] Article available free on PMC after 21/05/2016 Related Publications
Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by α-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes α-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile.

Jain P, Keating M, Thompson PA, et al.
High fluorescence in situ hybridization percentage of deletion 11q in patients with chronic lymphocytic leukemia is an independent predictor of adverse outcome.
Am J Hematol. 2015; 90(6):471-7 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
We have analyzed patients with previously untreated chronic lymphocytic leukemia with del11q fluorescence in situ hybridization (FISH) abnormality (n = 196) in this study. Detection of the 11q22.3 used a multicolor FISH technique. Patients with del11q fell into two major FISH subsets-sole del11q (n = 64) and del11q with del13q (n = 132). FISH subsets were compared using the median del11q FISH% (>58%, high vs. ≤58%, low). Overall survival (OS) and time to first treatment (TTFT) were estimated using Kaplan-Meier plots (log rank). Multivariate analysis was performed to assess the association between FISH% of del11q and outcomes. Patients with sole del11q were similar to del11q with del13q in terms of TTFT and OS. Patients with high FISH% of del11q had significantly shorter OS and TTFT as compared with patients with low FISH%, particularly in sole del11q; this negative impact of high FISH% of del11q on OS and TTFT was diminished with coexistent del13q. In multivariate analysis, high FISH% of del11q was a significant predictor for shorter OS and TTFT. A comparison of these del11q subsets with a separate cohort of (n = 673) previously untreated patients with sole del13q showed that the high FISH% del11q cohort had a significantly shorter TTFT and OS. In addition, bulky disease by physical examination or computed tomography imaging was infrequent at presentation in patients with del11q. High FISH% of del11q can reliably discriminate higher risk patients with chronic lymphocytic leukemia. Presence of coexistent del13q should be accounted for while prognosticating patients with del11q.

Berg V, Rusch M, Vartak N, et al.
miRs-138 and -424 control palmitoylation-dependent CD95-mediated cell death by targeting acyl protein thioesterases 1 and 2 in CLL.
Blood. 2015; 125(19):2948-57 [PubMed] Related Publications
Resistance toward CD95-mediated apoptosis is a hallmark of many different malignancies, as it is known from primary chronic lymphocytic leukemia (CLL) cells. Previously, we could show that miR-138 and -424 are downregulated in CLL cells. Here, we identified 2 new target genes, namely acyl protein thioesterase (APT) 1 and 2, which are under control of both miRs and thereby significantly overexpressed in CLL cells. APTs are the only enzymes known to promote depalmitoylation. Indeed, membrane proteins are significantly less palmitoylated in CLL cells compared with normal B cells. We identified APTs to directly interact with CD95 to promote depalmitoylation, thus impairing apoptosis mediated through CD95. Specific inhibition of APTs by siRNAs, treatment with miRs-138/-424, and pharmacologic approaches restore CD95-mediated apoptosis in CLL cells and other cancer cells, pointing to an important regulatory role of APTs in CD95 apoptosis. The identification of the depalmitoylation reaction of CD95 by APTs as a microRNA (miRNA) target provides a novel molecular mechanism for how malignant cells escape from CD95-mediated apoptosis. Here, we introduce palmitoylation as a novel posttranslational modification in CLL, which might impact on localization, mobility, and function of molecules, survival signaling, and migration.

Sun C, Wiestner A
Prognosis and therapy of chronic lymphocytic leukemia and small lymphocytic lymphoma.
Cancer Treat Res. 2015; 165:147-75 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course that has guided treatment principles in as much as anti-leukemic therapy is reserved for patients with active disease. This heterogeneity is somewhat dissected by prognostic markers, many of which represent pathogenic mechanisms. Recently, the introduction of highly active targeted agents and maturing data on predictive markers may lead to more individualized therapeutic approaches. In this chapter, we review key prognostic markers, current and emerging therapy, and will attempt to outline a future "where the two may connect".

Balatti V, Rizzotto L, Miller C, et al.
TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia.
Proc Natl Acad Sci U S A. 2015; 112(7):2169-74 [PubMed] Article available free on PMC after 17/08/2015 Related Publications
B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia and dysregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease based on transgenic mouse studies. To determine a role of microRNAs on the pathogenesis of the aggressive form of CLL we studied regulation of TCL1 expression in CLL by microRNAs. We identified miR-3676 as a regulator of TCL1 expression. We demonstrated that miR-3676 targets three consecutive 28-bp repeats within 3'UTR of TCL1 and showed that miR-3676 is a powerful inhibitor of TCL1. We further showed that miR-3676 expression is significantly down-regulated in four groups of CLL carrying the 11q deletions, 13q deletions, 17p deletions, or a normal karyotype compared with normal CD19(+) cord blood and peripheral blood B cells. In addition, the sequencing of 539 CLL samples revealed five germ-line mutations in six samples (1%) in miR-3676. Two of these mutations were loss-of-function mutations. Because miR-3676 is located at 17p13, only 500-kb centromeric of tumor protein p53 (Tp53), and is codeleted with Tp53, we propose that loss of miR-3676 causes high levels of TCL1 expression contributing to CLL progression.

Baliakas P, Agathangelidis A, Hadzidimitriou A, et al.
Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations.
Blood. 2015; 125(5):856-9 [PubMed] Article available free on PMC after 29/01/2016 Related Publications
An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.

Till KJ, Pettitt AR, Slupsky JR
Expression of functional sphingosine-1 phosphate receptor-1 is reduced by B cell receptor signaling and increased by inhibition of PI3 kinase δ but not SYK or BTK in chronic lymphocytic leukemia cells.
J Immunol. 2015; 194(5):2439-46 [PubMed] Article available free on PMC after 29/01/2016 Related Publications
BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton's tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechanisms underlying this phenomenon are incompletely understood. In this study, we showed that the egress receptor, sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), was expressed at low levels in normal germinal centers and CLL lymph nodes in vivo but became upregulated on normal B cells and, to a variable and lesser extent, CLL cells following in vitro incubation in S1P-free medium. Spontaneous recovery of S1PR1 expression on normal B and CLL cells was prevented by BCR cross-linking, whereas treatment of CLL cells with idelalisib increased S1PR1 expression and migration toward S1P, the greatest increase occurring in cases with unmutated IgH V region genes. Intriguingly, ibrutinib and fostamatinib had no effect on S1PR1 expression or function. Conversely, chemokine-induced migration, which requires integrin activation and is essential for the entry of lymphocytes into lymph nodes as well as their retention, was blocked by ibrutinib and fostamatinib, but not idelalisib. In summary, our results suggest that different BCR signaling inhibitors redistribute CLL cells from lymph nodes into the blood through distinct mechanisms: idelalisib actively promotes egress by upregulating S1PR1, whereas fostamatinib and ibrutinib may reduce CLL cell entry and retention by suppressing chemokine-induced integrin activation.

Maroofi F, Amini S, Roshani D, et al.
Different frequencies and effects of ABCB1 T3435C polymorphism on clinical and laboratory features of B cell chronic lymphocytic leukemia in Kurdish patients.
Tumour Biol. 2015; 36(4):2863-8 [PubMed] Related Publications
Finding the effects of gene polymorphism on cancer pathogenesis is very desirable. The ATP-binding cassette is involved in drug metabolism, and the polymorphism of this gene may be an important risk factor in B cell chronic lymphocytic leukemia (B-CLL) or progression and/or response to chemotherapy agents. For the first time, the present study was aimed to evaluate the probable effects of ABCB1 T3435C polymorphism on clinical and laboratory features of Kurdish patients with B-CLL. This descriptive analytical case-control study was performed on 50 B-CLL patients and 100 healthy subjects. Serum levels of beta-2-microglobulin (B2M) and lactate dehydrogenase (LDH) and blood WBC, RBC, Plt and ESR were measured. The T3435C polymorphism of the ABCB1 gene was determined by PCR-RFLP. Concentration of serum and blood markers was significantly higher in the malignant group than in the benign subjects. The CC genotype had the highest frequency (66%) in the patient groups. There are no significant differences between the genotypes and type of treatment. Our results demonstrate the high frequency of C allele of ABCB1 T3435C in B-CLL patients with Kurdish ethnicity. We also show that this polymorphism has a significant risk factor in B-CLL. However, the effect of this polymorphism on clinical and laboratory characteristics of B-CLL patients was not significant.

Woroniecka R, Rymkiewicz G, Grygalewicz B, et al.
Cytogenetic and flow cytometry evaluation of Richter syndrome reveals MYC, CDKN2A, IGH alterations with loss of CD52, CD62L and increase of CD71 antigen expression as the most frequent recurrent abnormalities.
Am J Clin Pathol. 2015; 143(1):25-35 [PubMed] Related Publications
OBJECTIVES: Richter syndrome (RS) is a transformation of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into high-grade lymphoma. There are only limited data on flow cytometry (FCM) and cytogenetics in RS.
METHODS: In this study, FCM, classic cytogenetics (CC), and fluorescence in situ hybridization (FISH) were performed in eight RS cases.
RESULTS: Most cases of RS were characterized by a loss/decrease of CD52 and CD62L and increased CD71 expression. CC identified complex karyotypes, with losses of 9/9p and 17/17p as the most frequent in four of seven cases. Seven RS cases demonstrated MYC abnormalities. Disruptions of CDKN2A and IGH were identified in five of seven and four of seven RS cases, respectively.
CONCLUSIONS: Newly diagnosed RS is an oncologic emergency, and a quick diagnostic decision is crucial in clinical practice. Therefore, in patients with CLL/SLL and rapidly enlarging asymmetric lymphadenopathy and/or extranodal tumors, we strongly advise FCM of fine-needle aspiration biopsy (FNAB) material, including CD62L, CD52, and CD71 analysis as well as assessment of karyotype and at least MYC abnormalities by FISH of the same FNAB material. Loss of CD52 expression in RS most likely predicts resistance to alemtuzumab therapy, which is frequently used in CLL.

Strefford JC
The genomic landscape of chronic lymphocytic leukaemia: biological and clinical implications.
Br J Haematol. 2015; 169(1):14-31 [PubMed] Related Publications
Chronic lymphocytic leukaemia (CLL) remains at the forefront of the genetic analysis of human tumours, principally due its prevalence, protracted natural history and accessibility to suitable material for analysis. With the application of high-throughput genetic technologies, we have an unbridled view of the architecture of the CLL genome, including a comprehensive description of the copy number and mutational landscape of the disease, a detailed picture of clonal evolution during pathogenesis, and the molecular mechanisms that drive genomic instability and therapeutic resistance. This work has nuanced the prognostic importance of established copy number alterations, and identified novel prognostically relevant gene mutations that function within biological pathways that are attractive treatment targets. Herein, an overview of recent genomic discoveries will be reviewed, with associated biological and clinical implications, and a view into how clinical implementation may be facilitated.

Landau DA, Clement K, Ziller MJ, et al.
Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.
Cancer Cell. 2014; 26(6):813-25 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.

Swanton C, Beck S
Epigenetic noise fuels cancer evolution.
Cancer Cell. 2014; 26(6):775-6 [PubMed] Related Publications
Cancer is a disease of the genome and the epigenome. Previous studies have shown that genomic changes such as mutations, copy number variation, and genomic rearrangements drive cancer evolution. In this issue of Cancer Cell, Landau and colleagues add epigenomic changes, specifically locally disordered DNA methylation, to cancer's evolutionary trajectory.

Geller MD, Pei Y, Spurgeon SE, et al.
Chronic lymphocytic leukemia with a FGFR3 translocation: case report and literature review of an uncommon cytogenetic event.
Cancer Genet. 2014 Jul-Aug; 207(7-8):340-3 [PubMed] Related Publications
The t(4;14) (p16; q32) with fusion of the IGH (immunoglobulin heavy chain) and FGFR3 (fibroblast growth factor receptor 3) genes are rarely present in patients with chronic lymphocytic leukemia (CLL), with only two previously reported cases. We herein describe a unique case of CLL with the occurrence of a t(4;14) (p16;q32), trisomy 12, and deletion of 11q13-q23 in the same clonal cells. In contrast to myeloma, in which FGFR3 translocations are a common early cytogenetic hit, FGFR3 rearrangement in CLL appears to occur later in the disease course.

Gerrie AS, Huang SJ, Bruyere H, et al.
Population-based characterization of the genetic landscape of chronic lymphocytic leukemia patients referred for cytogenetic testing in British Columbia, Canada: the role of provincial laboratory standardization.
Cancer Genet. 2014 Jul-Aug; 207(7-8):316-25 [PubMed] Related Publications
Detection of recurrent chromosome abnormalities by fluorescence in situ hybridization (FISH) is an essential component of care in chronic lymphocytic leukemia (CLL) patients. In the province of British Columbia (BC), Canada, population 4.6 million, CLL patients receive uniform evaluation and therapy with FISH testing performed in three jurisdictions. The aims of this study were to (i) validate CLL-FISH testing among the BC cytogenetic laboratories to ensure standardization of results and (ii) characterize population-level CLL-FISH abnormalities by pooling provincial data. From 2004 to 2011, 585 consecutive patients underwent pretreatment CLL-FISH testing at laboratory A (50.1%), laboratory B (32.3%), or laboratory C (17.6%). For validation purposes, 26 CLL-FISH abnormalities were tested by each laboratory's protocol, with 91% result concordance. Discordant results involved percent abnormalities at or near cutoff values; therefore, a 10% universal cutoff was established when pooling results. Applying the universal cutoff to the provincial cohort, CLL-FISH abnormalities were detected in 74.9%: 54.9% 13q-, 18.8% +12, 8.5% 11q-, and 7.7% 17p-. In this large population-based cohort of patients referred for CLL-FISH testing, frequencies of abnormalities detected by FISH analysis were highly consistent with those reported in single-institution and clinical trial populations. Provinces or districts that work together to care for CLL patients can effectively pool data with appropriate laboratory validation to ensure standardization of results.

Xochelli A, Agathangelidis A, Kavakiotis I, et al.
Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia.
Immunogenetics. 2015; 67(1):61-6 [PubMed] Related Publications
Νext generation sequencing studies in Homo sapiens have identified novel immunoglobulin heavy variable (IGHV) genes and alleles necessitating changes in the international ImMunoGeneTics information system (IMGT) GENE-DB and reference directories of IMGT/V-QUEST. In chronic lymphocytic leukaemia (CLL), the somatic hypermutation (SHM) status of the clonotypic rearranged IGHV gene is strongly associated with patient outcome. Correct determination of this parameter strictly depends on the comparison of the nucleotide sequence of the clonotypic rearranged IGHV gene with that of the closest germline counterpart. Consequently, changes in the reference directories could, in principle, affect the correct interpretation of the IGHV mutational status in CLL. To this end, we analyzed 8066 productive IG heavy chain (IGH) rearrangement sequences from our consortium both before and after the latest update of the IMGT/V-QUEST reference directory. Differences were identified in 405 cases (5 % of the cohort). In 291/405 sequences (71.9 %), changes concerned only the IGHV gene or allele name, whereas a change in the percent germline identity (%GI) was noted in 114/405 (28.1 %) sequences; in 50/114 (43.8 %) sequences, changes in the %GI led to a change in the mutational set. In conclusion, recent changes in the IMGT reference directories affected the interpretation of SHM in a sizeable number of IGH rearrangement sequences from CLL patients. This indicates that both physicians and researchers should consider a re-evaluation of IG sequence data, especially for those IGH rearrangement sequences that, up to date, have a GI close to 98 %, where caution is warranted.

Ojha J, Ayres J, Secreto C, et al.
Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia.
Blood. 2015; 125(3):492-8 [PubMed] Article available free on PMC after 15/01/2016 Related Publications
Recent high-throughput sequencing and microarray studies have characterized the genetic landscape and clonal complexity of chronic lymphocytic leukemia (CLL). Here, we performed a longitudinal study in a homogeneously treated cohort of 12 patients, with sequential samples obtained at comparable stages of disease. We identified clonal competition between 2 or more genetic subclones in 70% of the patients with relapse, and stable clonal dynamics in the remaining 30%. By deep sequencing, we identified a high reservoir of genetic heterogeneity in the form of several driver genes mutated in small subclones underlying the disease course. Furthermore, in 2 patients, we identified convergent evolution, characterized by the combination of genetic lesions affecting the same genes or copy number abnormality in different subclones. The phenomenon affects multiple CLL putative driver abnormalities, including mutations in NOTCH1, SF3B1, DDX3X, and del(11q23). This is the first report documenting convergent evolution as a recurrent event in the CLL genome. Furthermore, this finding suggests the selective advantage of specific combinations of genetic lesions for CLL pathogenesis in a subset of patients.

Te Raa GD, Derks IA, Navrkalova V, et al.
The impact of SF3B1 mutations in CLL on the DNA-damage response.
Leukemia. 2015; 29(5):1133-42 [PubMed] Related Publications
Mutations or deletions in TP53 or ATM are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with ATM aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (n=110) containing ATM, SF3B1 and TP53 gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly, SF3B1 mutated samples without concurrent ATM and TP53 aberrations (sole SF3B1) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast, NOTCH1 or K/N-RAS mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole SF3B1 mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with SF3B1 mutations.

Li YY, Tian T, Zhang R, et al.
Association between polymorphism of GLI1 gene SNP rs2228226 and chronic lymphocytic leukemia in Chinese population.
Med Oncol. 2014; 31(12):294 [PubMed] Related Publications
A non-synonymous single-nucleotide polymorphism (SNP) (rs2228226C>G), in exon 12 of glioma-associated oncogene homolog 1 (GLI1) (Q1100E), encodes a change from glutamine to glutamic acid (Q1100E). The variant GLI1 protein exhibited reduced transactivation function in vivo, decreasing the ability of activating hedgehog signal, which has been proposed as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL). The GLI1 Q1100E (NCBI SNP ID: rs2228226) genotypes in 155 CLL patients were detected by direct sequencing. The difference between frequencies of GLI1 Q1100E genotype among CLL patients and controls was statistically significant (p < 0.001). Logistic regression analysis revealed that in comparison with G/G, GLI1 SNP1100 C/C genotype was associated with a significantly increased risk of CLL (OR 3.787, 95% CI 1.814-7.907, p < 0.001). Compared with the SNP1100 C/G genotype, C/C genotype significantly increased the risk of CLL (OR 3.860, 95% CI 1.827-8.153, p < 0.001). In addition, combining C/G with G/G, C/C genotype also significantly increased the risk of CLL (OR 3.820, 95% CI 1.885-7.742, p < 0.001). The comparison between frequencies of C and G allele of GLI1 was also statistically significant (p = 0.004). In the entire cohort, SNP1100 genotypes were found in association with Binet stage (p = 0.045) and trisomy 12 (p = 0.036). By comparing C/C with G allele (C/G+G/G) genotype, there was a significant correlation with trisomy 12 (p = 0.013). This study demonstrated that GLI1 Q1100E polymorphism was closely associated with CLL. C/C genotype contributes to the risk of developing CLL and correlates with trisomy 12. Patients with trisomy 12 are susceptible group of CLL.

Sutton LA, Rosenquist R
Clonal evolution in chronic lymphocytic leukemia: impact of subclonality on disease progression.
Expert Rev Hematol. 2015; 8(1):71-8 [PubMed] Related Publications
In recent years, next-generation sequencing has unraveled the molecular landscape in chronic lymphocytic leukemia with the discovery of a number of recurrently mutated genes. Mutations in several of these genes, such as NOTCH1, SF3B1 and BIRC3, are linked to a more aggressive disease with early disease progression, short time-to-first-treatment and even chemorefractoriness. Although in its infancy, we have also begun to understand the complex dynamics of subclonal diversity and its impact on disease outcome. From pioneering studies, we know that certain genetic events are found in the majority of chronic lymphocytic leukemia cells and are considered as 'clonal driver mutations' (e.g., +12, 13q-), whereas others, present only in a fraction of the tumor, are deemed to be 'subclonal driver mutations' for example, TP53 and SF3B1. Over the coming years, we need to gain a deeper insight into the dynamics of this subclonal architecture to understand how, at an individual level, chronic lymphocytic leukemia patients should be followed, which will be particularly relevant as novel targeted therapies begin to emerge.

Malcikova J, Stano-Kozubik K, Tichy B, et al.
Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia.
Leukemia. 2015; 29(4):877-85 [PubMed] Article available free on PMC after 15/01/2016 Related Publications
In chronic lymphocytic leukemia (CLL), the worst prognosis is associated with TP53 defects with the affected patients being potentially directed to alternative treatment. Therapy administration was shown to drive the selection of new TP53 mutations in CLL. Using ultra-deep next-generation sequencing (NGS), we performed a detailed analysis of TP53 mutations' clonal evolution. We retrospectively analyzed samples that were assessed as TP53-wild-type (wt) by FASAY from 20 patients with a new TP53 mutation detected in relapse and 40 patients remaining TP53-wt in relapse. Minor TP53-mutated subclones were disclosed in 18/20 patients experiencing later mutation selection, while only one minor-clone mutation was observed in those patients remaining TP53-wt (n=40). We documented that (i) minor TP53 mutations may be present before therapy and may occur in any relapse; (ii) the majority of TP53-mutated minor clones expand to dominant clone under the selective pressure of chemotherapy, while persistence of minor-clone mutations is rare; (iii) multiple minor-clone TP53 mutations are common and may simultaneously expand. In conclusion, patients with minor-clone TP53 mutations carry a high risk of mutation selection by therapy. Deep sequencing can shift TP53 mutation identification to a period before therapy administration, which might be of particular importance for clinical trials.

Mutlu P, Yalcin S, Elci P, et al.
Association of -174G/C interleukin/6 gene polymorphism with the risk of chronic lymphocytic, chronic myelogenous and acute myelogenous leukemias in Turkish patients.
J BUON. 2014 Jul-Sep; 19(3):787-91 [PubMed] Related Publications
PURPOSE: The purpose of this study was to evaluate the relationship between -174G/C interleukin-6 (IL-6) gene promoter polymorphism and susceptibility to chronic lymphocytic (CLL), chronic myelogenous (CML) and acute myelogenous leukemia (AML) in Turkish patients.
METHODS: The frequencies of -174G/C polymorphism were studied in 23 unrelated CLL, 25 CML and 17 AML patients and 30 healthy individuals. Single nucleotide polymorphisms (SNPs) were genotyped by the PCR-RFLP method.
RESULTS: A higher prevalence of the C allele was found in CLL, CML and AML patients. However, there were no statistically significant differences regarding either the genotype or the allelic frequencies of the -174G/C polymorphism between CLL, CML and AML cases.
CONCLUSIONS: These results indicate that C allele is associated with risk of CLL, CML and AML susceptibility in Turkish patients.

Chastain EC, Duncavage EJ
Clinical prognostic biomarkers in chronic lymphocytic leukemia and diffuse large B-cell lymphoma.
Arch Pathol Lab Med. 2015; 139(5):602-7 [PubMed] Related Publications
CONTEXT: Diffuse large B-cell lymphoma and chronic lymphocytic leukemia are 2 of the most common B-cell lymphomas in adults. Both diffuse large B-cell lymphoma and chronic lymphocytic leukemia share heterogeneous outcomes, and the use of prognostic biomarkers to better stratify risk in these patients has now become commonplace.
OBJECTIVE: To review chronic lymphocytic leukemia and diffuse large B-cell lymphoma biomarkers commonly used in the clinical laboratory, which can be divided into the following 3 main groups by testing methodology: chromosomal based (including fluorescence in situ hybridization and cytogenetics), expression based (including immunohistochemistry and flow cytometry), and DNA based (including gene sequencing for somatic mutations and IGVH mutational status).
DATA SOURCES: Review of recent literature.
CONCLUSIONS: In chronic lymphocytic leukemia, important biomarkers include expression of CD38 and ZAP-70, IGVH mutational status, somatic mutations in TP53 and NOTCH1, and abnormalities in chromosomes 11, 12, 13q, and 17. In diffuse large B-cell lymphoma, important biomarkers include chromosomal rearrangement of BCL2, BCL6, and MYC and expression of CD5, BCL2, and CD43, as well as somatic mutations in TP53 and BCL6.

Gragert L, Fingerson S, Albrecht M, et al.
Fine-mapping of HLA associations with chronic lymphocytic leukemia in US populations.
Blood. 2014; 124(17):2657-65 [PubMed] Article available free on PMC after 15/01/2016 Related Publications
Chronic lymphocytic leukemia (CLL) displays remarkable ethnic predisposition for whites, with relative sparing of African-American and Asian populations. In addition, CLL displays among the highest familial predispositions of all hematologic malignancies, yet the genetic basis for these differences is not clearly defined. The highly polymorphic HLA genes of the major histocompatibility complex play a central role in immune surveillance and confer risk for autoimmune and infectious diseases and several different cancers, the role for which in the development of CLL has not been extensively investigated. The National Marrow Donor Program/Be The Match has collected HLA typing from CLL patients in need of allogeneic hematopoietic stem cell transplant and has recruited millions of volunteers to potentially donate hematopoietic stem cells. HLA genotypes for 3491 US white, 397 African-American, and 90 Hispanic CLL patients were compared with 50 000 controls per population from the donor registry. We identified several HLA alleles associated with CLL susceptibility in each population, reconfirming predisposing roles of HLA-A*02:01 and HLA-DRB4*01:01 in whites. Associations for haplotype DRB4*01:01∼DRB1*07:01∼DQB1*03:03 were replicated across all 3 populations. These findings provide a comprehensive assessment of the role of HLA in the development of severe CLL.

Rana S, Shahid A, Ullah H, Mahmood S
Lack of association of the NPAS2 gene Ala394Thr polymorphism (rs2305160:G>A) with risk of chronic lymphocytic leukemia.
Asian Pac J Cancer Prev. 2014; 15(17):7169-74 [PubMed] Related Publications
BACKGROUND: NPAS2 is a product of the circadian clock gene. It acts as a putative tumor suppressor by playing an important role in DNA damage responses, cell cycle control and apoptosis. Chronic lymphocytic leukemia (CLL) appears to be an apoptosis related disorder and alteration in the NPAS2 gene might therefore be directly involved in the etiology of CLL. Here, the Ala394Thr polymorphism (rs2305160:G>A) in the NPAS2 gene was genotyped and melatonin concentrations were measured in a total of seventy-four individuals, including thirty-seven CLL cases and an equal number of age- and sex-matched healthy controls in order to examine the effect of NPAS2 polymorphism and melatonin concentrations on CLL risk in a Pakistani population.
MATERIALS AND METHODS: Genotyping of rs2305160:G>A polymorphism at NPAS2 locus was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Melatonin concentrations were determined by enzyme linked immunosorbent assay (ELISA). Statistical analysis was performed using Statistical Package for Social Sciences software.
RESULTS: Our results demonstrated no association of the variant Thr genotypes (Ala/ Thr and Thr/Thr) with risk of CLL. Similarly, no association of rs2305160 with CLL was observed in either females or males after stratification of study population on a gender basis. Moreover, when the subjects with CLL were further stratified into shift-workers and non-shift-workers, no association of rs2305160 with CLL was seen in either case. However, significantly low serum melatonin levels were observed in CLL patients as compared to healthy subjects (p<0.05). Also, lower melatonin levels were seen in shift-workers as compared to non-shift-workers (p<0.05). There was no significant difference (p>0.05) in the melatonin levels across NPAS2 genotypes in all subjects, subjects with CLL who were either shift workers or non-shift-workers. General Linear Model (GLM) univariate analysis revealed no significant association (p>0.05) of the rs2305160 polymorphism of the NPAS2 gene with melatonin levels in any of the groups.
CONCLUSIONS: While low melatonin levels and shift-work can be considered as one of the risk factors for CLL, the NPAS2 rs2305160 polymorphism does not appear to have any association with risk of CLL in our Pakistani population.

Komarova NL, Burger JA, Wodarz D
Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL).
Proc Natl Acad Sci U S A. 2014; 111(38):13906-11 [PubMed] Article available free on PMC after 15/01/2016 Related Publications
The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is a new targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib is given orally on a continuous schedule and induces durable remissions in the majority of CLL patients. However, a small proportion of patients initially responds to the BTKi and then develops resistance. Estimating the frequency, timing, and individual risk of developing resistance to ibrutinib, therefore, would be valuable for long-term management of patients. Computational evolutionary models, based on measured kinetic parameters of patients, allow us to approach these questions and to develop a roadmap for personalized prognosis and treatment management. Our kinetic models predict that BTKi-resistant mutants exist before initiation of ibrutinib therapy, although they only comprise a minority of the overall tumor burden. Furthermore, we can estimate the time required for resistant cells to grow to detectable levels. We predict that this can be highly variable, depending mostly on growth and death rates of the individual CLL cell clone. For a specific patient, this time can be predicted with a high degree of certainty. Our model can thus be used to predict for how long ibrutinib can suppress the disease in individual patients. Furthermore, the model can suggest whether prior debulking of the tumor with chemo-immunotherapy can prolong progression-free survival under ibrutinib. Finally, by applying the models to data that document progression during ibrutinib therapy, we estimated that resistant mutants might have a small (<2%) mean fitness advantage in the absence of treatment, compared with sensitive cells.

Diamantopoulos PT, Sofotasiou M, Papadopoulou V, et al.
PARP1-driven apoptosis in chronic lymphocytic leukemia.
Biomed Res Int. 2014; 2014:106713 [PubMed] Article available free on PMC after 15/01/2016 Related Publications
Chronic lymphocytic leukemia (CLL) is considered a malignancy resulting from defects in apoptosis. For this reason, targeting apoptotic pathways in CLL may be valuable for its management. Poly [ADP-ribose] polymerase 1 (PARP1) is the main member of a family of nuclear enzymes that act as DNA damage sensors. Through binding on DNA damaged structures, PARP1 recruits repair enzymes and serves as a survival factor, but if the damage is severe enough, its action may lead the cell to apoptosis through caspase activation, or necrosis. We measured the PARP1 mRNA and protein pretreatment levels in 26 patients with CLL and the corresponding posttreatment levels in 15 patients after 3 cycles of immunochemotherapy, as well as in 15 healthy blood donors. No difference was found between the pre- and posttreatment levels of PARP1, but we found a statistically significant relative increase of the 89 kDa fragment of PARP1 that is cleaved by caspases in the posttreatment samples, indicating PARP1-related apoptosis in CLL patients after treatment. Our findings constitute an important step in the field, especially in the era of PARP1 inhibitors, and may serve as a base for future clinical trials with these agents in CLL.

Queirós AC, Villamor N, Clot G, et al.
A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact.
Leukemia. 2015; 29(3):598-605 [PubMed] Related Publications
Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n=211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P<0.001) and VH usage (P<0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P<0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P<0.001) along with Binet stage (P<0.001). These findings were corroborated in a validation series (n=97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.

Maimaitili Y, Guzailinuer W, Wang X, et al.
[Detection of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia by fluorescence in situ hybridization and its clinical significance].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(4):499-503 [PubMed] Related Publications
OBJECTIVE: To investigate the presence of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia and its clinical significance.
METHODS: Interphase fluorescence in situ hybridization (FISH) was used to detect the p53 gene deletion in 77 patients with CLL. Presence of the deletion and its association with clinical and laboratory features as well as prognostic factors were analyzed. Kaplan-Meier method was used to calculate survivals, and the results were compared using a Log-rank test.
RESULTS: p53 gene deletion was found in 10 (12.9%) of the patients but none from the control group (P<0.05). The deletion was found in 12.5% (4/32) of ethnic Hans and 13.3% (6/45) of ethnic Uyghurs (P>0.05). No significant different distribution of p53 gene deletion was found in regard to sex, age, ethnicity, peripheral blood cell count (except for Hb) or the levels of lactate dehydrogenase, β2-micro globulin and CD38 (P>0.05). The deletion rate was higher in the group with high expression of ZAP-70 and patients with advanced stage disease than that in the group of low expression and early-stage CLL (P<0.05). Among 20 patients who received fludarabine therapy, the overall remission rate for those with p53 gene deletion (20%) was lower than those without (75%) (P<0.05). With a median follow-up time of 39.0 (8.0-136.0) months, 11 cases had died (14.3%), among them, 7 cases died from CLL and related complications, and all of them were founded p53 gene deletion. In patients with p53 gene deletion, the progression-free survival (18 months) was shorter than those without the deletion (55 months) (P<0.05).
CONCLUSION: The p53 gene deletion has been found in more than 10% of patients with CLL, and the deletion rate did not significantly differ between ethnic Han and Uyghur patients. The deletion is associated with advanced stage of the disease. High-level ZAP-70 expression and the presence of p53 deletion are associated with shorter survival and poor response to fludarabine containing therapy. Therefore, drugs affecting the p53 signaling pathway should be avoided.

Bergh AC, Evaldsson C, Pedersen LB, et al.
Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia.
Haematologica. 2014; 99(11):1722-30 [PubMed] Article available free on PMC after 15/01/2016 Related Publications
Chronic lymphocytic leukemia B cells express auto/xeno antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde that is present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen for analysis of downstream B-cell receptor-signal transduction events, since it is more faithful to B-cell physiology than anti-IgM. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen binding induced prompt receptor clustering followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca(2+) mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase 1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48-h culture in the absence of antigen in half of the cases. Toll-like receptor 9-ligand was found to breach the B-cell receptor-signaling incompetence in 5 of 12 cases pointing to intra-subset heterogeneity. Altogether, this study supports B-cell receptor unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia, indicating that these cells proliferate by other mechanisms that may override B-cell receptor silencing brought about in a context of self-tolerance/anergy. These novel findings have implications for the understanding of chronic lymphocytic leukemia pathobiology and therapy.

Benner A, Mansouri L, Rossi D, et al.
MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis.
Haematologica. 2014; 99(8):1285-91 [PubMed] Article available free on PMC after 15/01/2016 Related Publications
A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.

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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