Alternative titles; symbols
SNOMEDCT: 51092000, 92814006; ICD10CM: C91.1, C91.10; ICD9CM: 204.1; ORPHA: 67038; DO: 1040;
A number sign (#) is used with this entry because chronic lymphocytic leukemia (CLL) is associated with genetic and epigenetic changes in multiple genes.
Chronic lymphocytic leukemia (CLL) is a common neoplasia of B lymphocytes in which these cells progressively accumulate in the bone marrow, blood, and lymphoid tissues. The clinical evolution of the disorder is heterogeneous, with some patients having indolent disease and others having aggressive disease and short survival (summary by Quesada et al., 2012).
Genetic Heterogeneity of Susceptibility to Chronic Lymphocytic Leukemia
Susceptibility loci have been mapped to chromosomes 11p11 (CLLS1; 609630) and 13q14 (CLLS2; 109543) by genomewide linkage analysis and translocation studies, respectively. Susceptibility mapping to chromosome 9q34 (CLLS3; 612557) is associated with downregulation of the DAPK1 gene (600831). Genomewide association studies have identified susceptibility loci on chromosomes 6p25.3 (CLLS4; 612558) and 11q24.1 (CLLS5; 612559).
Wiley et al. (2002) noted that CLL is the most frequent type of leukemia in the developed world and results in the progressive accumulation of mature CD5 (153340)-positive B lymphocytes in blood and bone marrow of the affected person. Anemia and thrombocytopenia are features of advanced disease, but recurrent infections and splenomegaly, with or without lymphadenopathy, arise at all stages of CLL. Leukemic CD5-positive B lymphocytes have reduced ability to undergo apoptosis in vivo, a feature generally attributed to the antiapoptotic effects of overexpression of BCL2, although a defect in a proapoptotic pathway might also contribute to the prolonged survival of B lymphocytes in individuals with CLL.
O'Keefe et al. (2002) reported 2 adults, each with a pseudohypopyon (accumulation of tumor cells in the anterior chamber of the eye) due to B-cell lymphoma. In 1 patient, the ocular findings were the presenting signs; the other pseudohypopyon was found in a patient with known abdominal lymphoma. The authors concluded that pseudohypopyons may represent either the initial manifestation or a later complication of systemic lymphoma, similar to what had been reported in acute leukemia.
Chronic lymphocytic leukemia seems especially prone to familial occurrence. Studies of a large number of families (Gunz et al., 1975) indicated that the familial incidence of CLL is nearly 3 times higher than that expected for the general population. The first report of identical twins with CLL was that by Dameshek et al. (1929). Furbetta and Solinas (1963) reported affected grandfather, son, and grandson. Fraumeni et al. (1969) reported familial aggregation of chronic lymphocytic leukemia associated with immune defects in 3 sibs.
Branda et al. (1978) studied lymphocytes in a mother and son with chronic lymphocytic leukemia. Morphologic, functional and surface marker characteristics were very similar, as was the impairment of cellular and humoral immunity. Blattner et al. (1979) reported additional information on the family, including HLA studies and description of nodular, poorly differentiated lymphocytic lymphoma in the daughter of the proband.
Conley et al. (1980) found an increased frequency of chronic lymphocytic leukemia and also of autoimmune disease (hyperthyroidism, pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus) in families of patients with CLL. They concluded that genetic factors in these families disturb the regulation of the immune system.
Lynch et al. (2002) described a family in which the father and all 4 of his children had CLL. All of the children were male, and 2 were identical twins. CLL was diagnosed at the age of 77 in the father, at the ages of 56 and 54 in the identical twins, and at the ages of 47 and 39 in the other brothers. See 612557.
Goldin et al. (2004) used the Swedish Family Cancer Database to test for increased familial risks of CLL and other lymphoproliferative tumors. They found that relatives of cases were at significantly increased risk for CLL (relative risk (RR) = 7.52), for non-Hodgkin lymphoma (605027) (RR = 1.45), and for Hodgkin lymphoma (236000) (RR = 2.35). CLL risks were similar in parents, sibs, and offspring of cases, in male and female relatives, and were not affected by the case's age at diagnosis. Anticipation was not significant when analyzed using life table methods. Goldin et al. (2004) concluded that the familial component of CLL is shared with other lymphoproliferative malignancies, suggesting common genetic pathways; however, because clinically diagnosed CLL is uncommon, absolute excess risk to relatives is small.
Genetic Anticipation
Horwitz et al. (1996) reported evidence of anticipation in autosomal dominant chronic lymphocytic leukemia (p = 0.008). In 18 affected individuals from 7 pedigrees with autosomal dominant CLL, the mean age of onset in the parental generation was 66 years, versus 51 years in the younger generation. Based on this evidence of anticipation, Horwitz et al. (1996) suggested that dynamic mutations of unstable DNA sequence repeats could be a common mechanism of inherited hematopoietic malignancy. They proposed 3 possible candidate chromosomal regions for familial leukemia with anticipation: 21q22.1-22.2, 11q23.3 in the vicinity of the CBL2 gene (165360), and 16q22 in the vicinity of the CBFB gene (121360).
In a study of 13 families with CLL in 2 successive generations, Goldin et al. (1999) found evidence of anticipation, i.e., earlier disease onset in generation 2. They ruled out various biases that could account for the finding, and stated that they planned to look for expanded trinucleotide repeats in candidate genes in families showing anticipation.
Among 7 CLL families with 2 affected generations showing anticipation (mean presentation parental age of onset 78 years; mean second generation age of onset 50 years), Auer et al. (2006) found no trinucleotide repeat (TNR) expansions in DNA isolated from malignant B cells at 10 CCG- and CAG-repeat loci within the genome that have previously been associated with the phenomenon of anticipation in other disorders. Transmission of repeats followed a mendelian pattern of inheritance in both the control and diseased families. There was also no evidence for TNR expansion among samples from patients with sporadic CLL. There was some evidence for minor differences in the frequency of certain allele lengths present in the patient samples at certain loci.
Blattner et al. (1976) reported CLL in 4 of 5 sibs and their father. Follow-up by Neuland et al. (1983) showed spontaneous regression of the disease in 1 sib and shifts in the clinical pattern in the others. The unaffected sib developed lung cancer. Two CLL patients had abnormality of chromosome 12: trisomy in 1 and a mixture of dicentrics and translocations involving chromosome 12 in the other. In this same family, Shen et al. (1987) found that 2 brothers had rearrangement of the same heavy-chain variable region gene. Shen et al. (1987) suggested that the particular V(H) gene, which had an unusual DNA sequence, defined a previously unrecognized V(H) gene family. It was thought to be representative of the genome by, at most, 4 homologous sequences.
Translocations Involving 11q13 and 14q32
Tsujimoto et al. (1984) cloned the chromosomal breakpoint of CLL cells of the B-cell type carrying t(11;14)(q13;q32). The breakpoint was in the joining segment of the heavy chain locus on chromosome 14. A probe specific for chromosome 11 that mapped immediately 5-prime to the breakpoint on 14q+ detected a rearrangement of the homologous genomic DNA segment in CLL cells; DNA from a diffuse large cell lymphoma with the t(11;14) translocation showed the same rearrangement. This rearranged DNA segment was not present in Burkitt lymphoma cells with the t(8;14) translocation or in nonneoplastic human lymphoblastoid cells. Tsujimoto et al. (1984) concluded that the gene on 11q13, which the authors termed BCL1 (CCND1; 168461), is implicated in the malignant transformation of cells carrying the t(11;14) translocation.
In 2 different cases of B-cell CLL, Tsujimoto et al. (1985) found that the breakpoints on chromosome 11 were within 8 nucleotides of each other and the breakpoints on chromosome 14 involved the J4 DNA segment of the Ig heavy chain segment (see, e.g., IGHV; 147070). Because they detected a 7mer-9mer signal-like sequence with a 12-base-long spacer on the normal chromosome 11 close to the breakpoint, the authors speculated that the t(11;14) chromosome translocation in CLL may be sequence specific and may involve the recombination system for immunoglobulin V-D-J gene segment joining.
Translocation t(14;19)(q32;q13.1) is also a recurring translocation in the neoplastic cells of patients with CLL. In 1 such patient, McKeithan et al. (1987) analyzed the leukemic cells with probes from the immunoglobulin heavy-chain locus. Using a probe for the IGHA1 gene (146900), they detected a rearranged band by Southern blot analysis. After cloning and mapping, a subclone (BCL3; 109560) was shown to be from chromosome 19 by analysis of human-mouse somatic cell hybrids, confirming that the rearranged band contained the translocation breakpoint junction.
Other Cytogenetic Abnormalities
Espinet et al. (2003) described a sister and brother, 63 and 61 years old at examination, respectively, with B-cell CLL with different abnormal karyotypes detected by conventional cytogenetics: deletion of 7q32 in the sister and an insertion in 1p36 and deletion of 6q21 in the brother. Both sibs had a del(13)(q14) at the D13S319 locus, detected by interphase FISH.
The most frequent deletion of genomic DNA in CLL occurs in chromosome 13q14. This deletion is evident in about 50% of cases and is associated with a long interval between diagnosis and the need for treatment, the so-called treatment-free interval (Dohner et al., 2000). The 13q14 deletion is frequently the sole abnormality in CLL and other types of cancers (Calin et al., 2005).
Ng et al. (2007) identified a deletion at chromosome 13q14 in 11 (85%) of 13 patients with hereditary CLL studied by FISH analysis. Fine mapping of the 13q region found that affected members of 4 families with CLL shared a minimally deleted 3.68-Mb candidate region on chromosome 13q21.33-q22.2 between D13S1324 and D13S162. In 1 family, all affected individuals with CLL had deletions in 13q14 and shared a haplotype at 13q21.33-q22.2, suggesting that inherited factors may predispose to CLL. Two asymptomatic sibs with CD5+ monoclonal B-cell lymphocytosis (MBL) carried the at-risk haplotype at 13q21.33-q22.2, one of whom also had a 13q14 deletion, suggesting a relationship between CLL and MBL. Ng et al. (2007) suggested that 13q24 deletions may represent a very early genomic change in a cascade of genetic events that predispose to developing CLL and/or MBL. Direct sequencing analysis detected no frameshift or nonsense mutations in the coding region of 13 genes in the chromosome 13q21-q22 region.
In a review of molecular diagnosis of hematologic cancers, Staudt (2003) noted that studies of immunoglobulin gene mutations in CLL cells suggested that CLL may be 2 distinct diseases. The presence of somatic mutations in the immunoglobulin genes of CLL cells defined a group of patients with stable or slowly progressive disease requiring late or no treatment. By contrast, the absence of immunoglobulin gene mutations in CLL cells defined a group of patients who had a progressive clinical course requiring early treatment. These 2 subtypes of CLL may also differ with respect to oncogenic mechanisms, since deletion of the ATM locus (607585) on chromosome 11q is associated with the absence of immunoglobulin gene mutations in CLL and with shortened survival in some patients (Staudt, 2003). Expression of the single most discriminating gene, ZAP70 (176947), distinguished these 2 subtypes with 93% accuracy (Wiestner et al., 2003). Whereas analysis of the immunoglobulin gene sequence would be a challenging and expensive test to introduce into routine clinical practice, a quantitative RT-PCR assay or protein-based assay for the expression of ZAP70 was feasible, as indicated in the work of Crespo et al. (2003).
In 14 patients with CLL who were concordant for IgV(H) mutation status, CD38 (107270) expression, and clinical behavior, Scielzo et al. (2005) observed that patients with poor prognoses had mostly constitutively phosphorylated HS1 protein (601306), whereas only a fraction of HS1 was phosphorylated in patients with good prognoses. When a larger cohort of 26 unselected patients was investigated, the survival curve of all 40 patients revealed that those with predominantly phosphorylated HS1 had a significantly shorter median survival time. Scielzo et al. (2005) studied the expression pattern of HS1 after B-cell receptor engagement and found that normal mature B cells stimulated by anti-IgM shifted the non- or less-phosphorylated form of HS1 toward the more-phosphorylated form, naive B cells showed both HS1 forms, and memory B cells expressed mainly the phosphorylated fraction. Scielzo et al. (2005) concluded that antigen stimulation plays a central role in CLL.
Puente et al. (2011) performed whole-genome sequencing of 4 cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified 4 genes that are recurrently mutated: NOTCH1 (190198), exportin-1 (XPO1; 602559), myeloid differentiation primary response gene-88 (MYD88; 602170), and kelch-like 6 (KLHL6; 614214). Somatic mutations in the NOTCH1 gene were found in 31 (12.2%) of 255 cases. Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are detected mainly in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicated that the recurrent NOTCH1, MYD88, and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease.
In a follow-up to the study of Puente et al. (2011), Quesada et al. (2012) used whole-exome sequencing of matched tumor and normal samples from 105 individuals with CLL to identify a median of 45 somatic mutations per case, involving 1,100 different genes. The number of protein-altering mutations per case was higher in those with somatic hypermutations in the variable regions of immunoglobulin genes (IGHV) than in those without such mutations. Among the 1,100 genes with somatic mutations, 78 genes were recurrently mutated, and 90% of patients had somatic mutations in at least 1 of the 78 recurrently mutated genes. Functional clustering analysis showed that many of the genes were involved in mRNA splicing pathways and transport and Toll-like receptor (see, e.g., TLR1, 601194) signaling and apoptosis. Specific mutated genes distinct from those reported by Puente et al. (2011) included SF3B1 (605590), POT1 (606478), CHD2 (602119), and LRP1B (608766). All POT1 somatic mutations appeared in tumors without IGHV region mutations, whereas CHD2 somatic mutations exclusively appeared in IGHV-mutated tumors. These findings supported the idea that different mechanisms are involved in disease development in CLL cases with and those without IGHV mutations. Sanger sequencing identified somatic mutations in the NOTCH1 gene in 25 (9.5%) of 260 cases of CLL, and somatic mutations in the SF3B1 gene were found in 27 (9.7%) of 279 cases of CLL. The SF3B1 gene encodes a protein involved in the spliceosomal U2 snRNP (RNU2-1; 180690), indicating an important role in gene expression. All SF3B1 mutations occurred in the nonidentical HEAT domains, and SF3B1-mutant cases showed enhanced expression of truncated mRNAs of various genes. Clinically, patients with SF3B1 mutations had faster disease progression and poorer overall survival compared to those with other mutations. No SF3B1 mutations were found in 156 cases of non-Hodgkin lymphoma (605027).
Wang et al. (2011) performed paired tumor and germline whole-exome and whole-genome sequencing from DNA samples in 91 patients with CLL. Nine genes were mutated at significant frequencies, including TP53 (191170) in 15% of patients, ATM (607585) in 9%, MYD88, in 10%, and NOTCH1 in 4%. Five novel genes were detected: SF3B1, ZMYM3 (300061), MAPK1 (176948), FBXW7 (606278), and DDX3X (300160). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene, with mutations occurring in 15% of patients. SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with CLL. Wang et al. (2011) discovered that tumor samples with mutations in SF3B1 had alterations in pre-mRNA splicing.
Puente et al. (2015) described a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. Puente et al. (2015) extended the number of CLL driver alterations, including changes in ZNF292 (616213), ZMYM3, ARID1A (603024) and PTPN11 (176876). Puente et al. (2015) also identified novel recurrent mutations in noncoding regions, including the 3-prime region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity, and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5 (167414). The accumulative number of driver alterations (0 to 4 or more) discriminated between patients with differences in clinical behavior.
Landau et al. (2015) identified 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 CLL and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These included previously unrecognized putative cancer drivers (RPS15, 180535; IKZF3, 606221), and collectively identified RNA processing and export, MYC activity, and MAPK signaling as central pathways involved in CLL. Clonality analysis of this large dataset further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pretreatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution.
For discussion of an association between CLL and somatic mutation in the GNB1 gene, see 139380.
Associations Pending Confirmation
Wiley et al. (2002) presented evidence that a single-nucleotide polymorphism of the purinergic receptor P2RX7 on chromosome 12q24 resulting in the substitution E496A (see 602566) occurred with increased frequency in patients with CLL, suggesting that it may be a susceptibility factor.
Calin et al. (2005) found that all 5 members with cancer in a kindred with familial CLL harbored a W149X polymorphism in the ARL11 gene (609351) on chromosome 13q14, whereas 2 unaffected members who were analyzed did not. The only member of this kindred who was homozygous for the polymorphism had kidney carcinoma and thyroid adenoma when she was less than 50 years old. In the third generation, 6 members, 1 of whom had received the diagnosis of essential thrombocythemia (a premalignant state), had the polymorphism; the other 5 members were less than 40 years old.
Calin et al. (2002) used positional cloning to identify 2 members of a class of small, noncoding RNAs, or microRNAs, miR15A (609703) and miR16-1 (609704), which are located in the smallest region of the deletion at 13q14 and are frequently deleted or downregulated in CLL cells. The finding that approximately 50% of the known human microRNAs are located at cancer-associated regions of the genome (Calin et al., 2004) suggests that microRNAs play a role in the pathogenesis of various human cancers. Calin et al. (2005) found a unique microRNA expression signature composed of 13 genes that differentiated cases of CLL with low levels of ZAP70 (176947) expression from those with high levels and cases with unmutated immunoglobulin heavy-chain variable-region gene, IgV(H) (see 147070), from those with mutated IgV(H). The same microRNA signature was also associated with the presence or absence of disease progression. They also identified a germline mutation in the primary precursor of miR16-1/miR15A (609704), which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germline or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (p less than 0.001).
Cimmino et al. (2005) determined that the first 9 nucleotides of miR15A and miR16-1 are complementary to bases in a central region of BCL2 cDNA. By miRNA microarray chip and Western blot analysis of CD5-positive lymphocytes from 4 normal individuals and of samples from 26 CLL patients, they found that low miR15A and miR16-1 levels and high BCL2 protein levels correlated with disease. Overexpression of either miRNA did not affect BCL2 mRNA stability but regulated BCL2 expression at the posttranscriptional level, and overexpression of miR15A or miR16-1 in megakaryocytic leukemia cells induced apoptosis.
To identify novel susceptibility loci for CLL, Slager et al. (2011) performed a genomewide association study in 407 CLL cases, of which 102 had a family history of CLL, and 296 controls. To identify loci specific to these familial CLL cases, they separately analyzed the subset of cases with a family history of CLL. They evaluated their top hits from these analyses in an additional sample of 252 familial CLL cases and 965 controls. In the subset of familial CLL cases, Slager et al. (2011) identified and confirmed a novel locus on chromosome 6p21.3 harboring the HLA-DQA1 (146880) and HLA-DRB5 (604776) genes. The region was tagged by 5 SNPs, the most significant of which was rs674313 in the HLA-DRB5 gene (risk allele T, combined p = 6.92 x 10(-9)). This locus showed no evidence of association among the sporadic CLL cases. The findings of Slager et al. (2011) supported the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. By linkage analysis, Bevan et al. (2000) had previously reported exclusion of an effect on CLL of genes within the MHC region on chromosome 6.
Berndt et al. (2013) conducted the largest metaanalysis for CLL to that time, including 4 genomewide association studies with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the metaanalysis, Berndt et al. (2013) identified 10 independent associated SNPs in 9 novel loci as well as an independent signal at a previously identified locus at chromosome 2q13.
Hamblin (2004) pointed out that with sensitive techniques, a monoclonal population of B lymphocytes that is indistinguishable from CLL cells may be found in the blood of 3.5% of persons older than 40 years of age.
In the early days of clinical cytogenetics, Gunz et al. (1962) described a chromosome abnormality in CLL affecting a small acrocentric chromosome, probably number 21, and designated it the Ch(1) (Christchurch) chromosome. The abnormality was reported in 6 cases, but was not found in any later cytogenetic studies. Almost a decade would pass before banding methods were described (Caspersson et al., 1970) and almost 2 decades before reliable methods of in situ hybridization were developed.
Auer, R. L., Dighiero, G., Goldin, L. R., Syndercombe-Court, D., Jones, C., McElwaine, S., Newland, A. C., Fegan, C. D., Caporaso, N., Cotter, F. E. Trinucleotide repeat dynamic mutation identifying susceptibility in familial and sporadic chronic lymphocytic leukemia. Brit. J. Haemat. 136: 73-79, 2006. [PubMed: 17116127] [Full Text: https://doi.org/10.1111/j.1365-2141.2006.06388.x]
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281-297, 2004. [PubMed: 14744438] [Full Text: https://doi.org/10.1016/s0092-8674(04)00045-5]
Berndt, S. I., Skibola, C. F., Joseph, V., Camp, N. J., Nieters, A., Wang, Z., Cozen, W., Monnereau, A., Wang, S. S., Kelly, R. S., Lan, Q., Teras, L. R., and 118 others. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nature Genet. 45: 868-876, 2013. [PubMed: 23770605] [Full Text: https://doi.org/10.1038/ng.2652]
Bevan, S., Catovsky, D., Matutes, E., Antunovic, P., Auger, M. J., Ben-Bassat, I., Bell, A., Berrebi, A., Gaminara, E. J., Junior, M. E., Mauro, F. R., Quabeck, K., and 10 others. Linkage analysis for major histocompatibility complex-related genetic susceptibility in familial chronic lymphocytic leukemia. Blood 96: 3982-3984, 2000. [PubMed: 11090088]
Blattner, W. A., Dean, J. H., Fraumeni, J. F., Jr. Familial lymphoproliferative malignancy: clinical and laboratory follow-up. Ann. Intern. Med. 90: 943-944, 1979. [PubMed: 155996] [Full Text: https://doi.org/10.7326/0003-4819-90-6-943]
Blattner, W. A., Naiman, J. L., Mann, D. L., Wimer, R. S., Dean, J. H., Fraumeni, J. F., Jr. Immunogenetic determinants of familial acute lymphocytic leukemia. Ann. Intern. Med. 89: 173-176, 1978. [PubMed: 307933] [Full Text: https://doi.org/10.7326/0003-4819-89-2-173]
Blattner, W. A., Strober, W., Muchmore, A. V., Blaese, R. M., Broder, S., Fraumeni, J. F., Jr. Familial chronic lymphocytic leukemia: immunologic and cellular characterization. Ann. Intern. Med. 84: 554-557, 1976. [PubMed: 818930] [Full Text: https://doi.org/10.7326/0003-4819-84-5-554]
Branda, R. F., Ackerman, S. K., Handwerger, B. S., Howe, R. B., Douglas, S. D. Lymphocyte studies in familial chronic lymphatic leukemia. Am. J. Med. 64: 508-514, 1978. [PubMed: 637060] [Full Text: https://doi.org/10.1016/0002-9343(78)90238-3]
Calin, G. A., Dumitru, C. D., Shimizu, M., Bichi, R., Zupo, S., Noch, E., Aldler, H., Rattan, S., Keating, M., Rai, K., Rassenti, L., Kipps, T., Negrini, M., Bullrich, F., Croce, C. M. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Nat. Acad. Sci. 99: 15524-15529, 2002. [PubMed: 12434020] [Full Text: https://doi.org/10.1073/pnas.242606799]
Calin, G. A., Ferracin, M., Cimmino, A., Di Leva, G., Shimizu, M., Wojcik, S. E., Iorio, M. V., Visone, R., Sever, N. I., Fabbri, M., Iuliano, R., Palumbo, T., and 11 others. A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. New Eng. J. Med. 353: 1793-1801, 2005. Note: Erratum: New Eng. J. Med. 354: 525 only, 2006; Erratum: New Eng. J. Med. 355: 533 only, 2006. [PubMed: 16251535] [Full Text: https://doi.org/10.1056/NEJMoa050995]
Calin, G. A., Sevignani, C., Dumitru, C. D., Hyslop, T., Noch, E., Yendamuri, S., Shimizu, M., Rattan, S., Bullrich, F., Negrini, M., Croce, C. M. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Nat. Acad. Sci. 101: 2999-3004, 2004. [PubMed: 14973191] [Full Text: https://doi.org/10.1073/pnas.0307323101]
Calin, G. A., Trapasso, F., Shimizu, M., Dumitru, C. D., Yendamuri, S., Godwin, A. K., Ferracin, M., Bernardi, G., Chatterjee, D., Baldassarre, G., Rattan, S., Alder, H., and 19 others. Familial cancer associated with a polymorphism in ARLTS1. New Eng. J. Med. 352: 1667-1676, 2005. [PubMed: 15843669] [Full Text: https://doi.org/10.1056/NEJMoa042280]
Caspersson, T., Zech, L., Johansson, C. Differential binding of alkylating fluorochromes in human chromosomes. Exp. Cell Res. 60: 315-319, 1970. [PubMed: 5422961] [Full Text: https://doi.org/10.1016/0014-4827(70)90523-9]
Cimmino, A., Calin, G. A., Fabbri, M., Iorio, M. V., Ferracin, M., Shimizu, M., Wojcik, S. E., Aqeilan, R. I., Zupo, S., Dono, M., Rassenti, L., Alder, H., Volinia, S., Liu, C., Kipps, T. J., Negrini, M., Croce, C. M. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Nat. Acad. Sci. 102: 13944-13949, 2005. Note: Erratum: Proc. Nat. Acad. Sci. 103: 2464-2465, 2006. [PubMed: 16166262] [Full Text: https://doi.org/10.1073/pnas.0506654102]
Conley, C. L., Misiti, J., Laster, A. J. Genetic factors predisposing to chronic lymphocytic leukemia and to autoimmune disease. Medicine 59: 323-334, 1980. [PubMed: 7001171] [Full Text: https://doi.org/10.1097/00005792-198009000-00001]
Crespo, M., Bosch, F., Villamor, N., Bellosillo, B., Colomer, D., Rozman, M., Marce, S., Lopez-Guillermo, A., Campo, E., Montserrat, E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. New Eng. J. Med. 348: 1764-1775, 2003. [PubMed: 12724482] [Full Text: https://doi.org/10.1056/NEJMoa023143]
Dameshek, W., Savitz, H. A., Arbor, B. Chronic lymphocytic leukemia in twin brothers aged fifty-six. JAMA 92: 1348-1349, 1929.
Dohner, H., Stilgenbauer, S., Benner, A., Leupolt, E., Krober, A., Bullinger, L., Dohner, K., Bentz, M., Lichter, P. Genomic aberrations and survival in chronic lymphocytic leukemia. New Eng. J. Med. 343: 1910-1916, 2000. [PubMed: 11136261] [Full Text: https://doi.org/10.1056/NEJM200012283432602]
Erikson, J., Finan, J., Tsujimoto, Y., Nowell, P. C., Croce, C. M. The chromosome 14 breakpoint in neoplastic B cells with the t(11;14) translocation involves the immunoglobulin heavy chain locus. Proc. Nat. Acad. Sci. 81: 4144-4148, 1984. [PubMed: 6429662] [Full Text: https://doi.org/10.1073/pnas.81.13.4144]
Espinet, B., Salido, M., Hernandez, J. A., Zamora, L., Bosch, M. A., Serrano, S., Sole, F. Cytogenetic findings in familial B-cell chronic lymphocytic leukemia: a report of two cases in a family. Cancer Genet. Cytogenet. 143: 172-173, 2003. [PubMed: 12781453] [Full Text: https://doi.org/10.1016/s0165-4608(02)00847-6]
Fraumeni, J. F., Vogel, C. L., DeVita, V. T. Familial chronic lymphocytic leukemia. Ann. Intern. Med. 71: 279-284, 1969. [PubMed: 4184386] [Full Text: https://doi.org/10.7326/0003-4819-71-2-279]
Furbetta, D., Solinas, P. Hereditary chronic lymphatic leukemia. In: Gedda, L. (ed.): Proceedings of the Second International Congress on Human Genetics, Rome, Sept. 6-12, 1961. Vol. 2. Rome: Instituto G. Mendel (pub.) 1963. Pp. 1078-1079.
Goldin, L. R., Pfeiffer, R. M., Li, X., Hemminki, K. Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood 104: 1850-1854, 2004. [PubMed: 15161669] [Full Text: https://doi.org/10.1182/blood-2004-01-0341]
Goldin, L. R., Sgambati, M., Marti, G. E., Fontaine, L., Ishibe, N., Caporaso, N. Anticipation in familial chronic lymphocytic leukemia. (Letter) Am. J. Hum. Genet. 65: 265-269, 1999. [PubMed: 10364544] [Full Text: https://doi.org/10.1086/302458]
Gunz, F., Dameshek, W. Chronic lymphatic leukemia in a family, including twin brothers and a son. JAMA 164: 1323-1325, 1957.
Gunz, F. W., Fitzgerald, P. H., Adams, A. An abnormal chromosome in chronic lymphocytic leukaemia. Brit. Med. J. 2: 1097-1099, 1962. [PubMed: 13951305] [Full Text: https://doi.org/10.1136/bmj.2.5312.1097]
Gunz, F. W., Gunz, J. P., Veale, A. M. O., Chapman, C. J., Houston, I. B. Familial leukaemia: a study of 909 families. Scand. J. Haemat. 15: 117-131, 1975. [PubMed: 1188315] [Full Text: https://doi.org/10.1111/j.1600-0609.1975.tb01063.x]
Hamblin, T. J. Predicting progression--ZAP-70 in CLL. New Eng. J. Med. 351: 856-857, 2004. [PubMed: 15329421] [Full Text: https://doi.org/10.1056/NEJMp048184]
Horwitz, M., Goode, E. L., Jarvik, G. P. Anticipation in familial leukemia. Am. J. Hum. Genet. 59: 990-998, 1996. [PubMed: 8900225]
Landau, D. A., Tausch, E., Taylor-Weiner, A. N., Stewart, C., Reiter, J. G., Bahlo, J., Kluth, S., Bozic, I., Lawrence, M., Bottcher, S., Carter, S. L., Cibulskis, K., and 19 others. Mutations driving CLL and their evolution in progression and relapse. Nature 526: 525-530, 2015. [PubMed: 26466571] [Full Text: https://doi.org/10.1038/nature15395]
Lynch, H. T., Weisenburger, D. D., Quinn-Laquer, B., Watson, P., Lynch, J. F., Sanger, W. G. Hereditary chronic lymphocytic leukemia: an extended family study and literature review. Am. J. Med. Genet. 115: 113-117, 2002. [PubMed: 12407690] [Full Text: https://doi.org/10.1002/ajmg.10686]
McKeithan, T. W., Rowley, J. D., Shows, T. B., Diaz, M. O. Cloning of the chromosome translocation breakpoint junction of the t(14;19) in chronic lymphocytic leukemia. Proc. Nat. Acad. Sci. 84: 9257-9260, 1987. [PubMed: 3122218] [Full Text: https://doi.org/10.1073/pnas.84.24.9257]
McPhedran, P., Heath, C. W., Jr., Lee, J. Patterns of familial leukemia. Ten cases of leukemia in two interrelated families. Cancer 24: 403-407, 1969. [PubMed: 5256260] [Full Text: https://doi.org/10.1002/1097-0142(196908)24:2<403::aid-cncr2820240224>3.0.co;2-l]
Neuland, C. Y., Blattner, W. A., Mann, D. L., Fraser, M. C., Tsai, S., Strong, D. M. Familial chronic lymphocytic leukemia. J. Nat. Cancer Inst. 71: 1143-1150, 1983. [PubMed: 6418939]
Ng, D., Toure, O., Wei, M.-H., Arthur, D. C., Abbasi, F., Fontaine, L., Marti, G. E., Fraumeni, J. F, Jr., Goldin, L. R., Caporaso, N., Toro, J. R. Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial chronic lymphocytic leukemia. Blood 109: 916-925, 2007. [PubMed: 17047154] [Full Text: https://doi.org/10.1182/blood-2006-03-011825]
O'Keefe, J. S., Sippy, B. D., Martin, D. F., Holden, J. T., Grossniklaus, H. E. Anterior chamber infiltrates associated with systemic lymphoma: report of two cases and review of the literature. Ophthalmology 109: 253-257, 2002. [PubMed: 11825804] [Full Text: https://doi.org/10.1016/s0161-6420(01)00934-4]
Puente, X. S., Bea, S., Valdes-Mas, R., Villamor, N., Gutierrez-Abril, J., Martin-Subero, J. I., Munar, M., Rubio-Perez, C., Jares, P., Aymerich, M., Baumann, T., Beekman, R., and 45 others. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526: 519-524, 2015. [PubMed: 26200345] [Full Text: https://doi.org/10.1038/nature14666]
Puente, X. S., Pinyol, M., Quesada, V., Conde, L., Ordonez, G. R., Villamor, N., Escaramis, G., Jares, P., Bea, S., Gonzalez-Diaz, M., Bassaganyas, L., Baumann, T., and 52 others. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475: 101-105, 2011. [PubMed: 21642962] [Full Text: https://doi.org/10.1038/nature10113]
Quesada, V., Conde, L., Villamor, N., Ordonez, G. R., Jares, P., Bassaganyas, L., Ramsay, A. J., Bea, S., Pinyol, M., Martinez-Trillos, A., Lopez-Guerra, M., Colomer, D., and 29 others. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nature Genet. 44: 47-52, 2012. [PubMed: 22158541] [Full Text: https://doi.org/10.1038/ng.1032]
Scielzo, C., Ghia, P., Conti, A., Bachi, A., Guida, G., Geuna, M., Alessio, M., Caligaris-Cappio, F. HS1 protein is differentially expressed in chronic lymphocytic leukemia patient subsets with good or poor prognoses. J. Clin. Invest. 115: 1644-1650, 2005. [PubMed: 15931393] [Full Text: https://doi.org/10.1172/JCI24276]
Shen, A., Humphries, C., Tucker, P., Blattner, F. Human heavy-chain variable region gene family nonrandomly rearranged in familial chronic lymphocytic leukemia. Proc. Nat. Acad. Sci. 84: 8563-8567, 1987. [PubMed: 3120193] [Full Text: https://doi.org/10.1073/pnas.84.23.8563]
Slager, S. L., Rabe, K. G., Achenbach, S. J., Vachon, C. M., Goldin, L. R., Strom, S. S., Lanasa, M. C., Spector, L. G., Rassenti, L. Z., Leis, J. F., Camp, N. J., Glenn, M., and 10 others. Genome-wide association study identifies a novel susceptibility locus at 6p21.3. Blood 117: 1911-1916, 2011. [PubMed: 21131588] [Full Text: https://doi.org/10.1182/blood-2010-09-308205]
Staudt, L. M. Molecular diagnosis of the hematologic cancers. New Eng. J. Med. 348: 1777-1785, 2003. Note: Erratum: New Eng. J. Med. 348: 2588 only, 2003. [PubMed: 12724484] [Full Text: https://doi.org/10.1056/NEJMra020067]
Tsujimoto, Y., Jaffe, E., Cossman, J., Gorham, J., Nowell, P. C., Croce, C. M. Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosome translocation. Nature 315: 340-343, 1985. [PubMed: 3923362] [Full Text: https://doi.org/10.1038/315340a0]
Tsujimoto, Y., Yunis, J., Onorato-Showe, L., Erikson, J., Nowell, P. C., Croce, C. M. Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 224: 1403-1406, 1984. [PubMed: 6610211] [Full Text: https://doi.org/10.1126/science.6610211]
Wang, L., Lawrence, M. S., Wan, Y., Stojanov, P., Sougnez, C., Stevenson, K., Werner, L., Sivachenko, A., DeLuca, D. S., Zhang, L., Zhang, W., Vartanov, A. R., and 17 others. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. New Eng. J. Med. 365: 2497-2506, 2011. [PubMed: 22150006] [Full Text: https://doi.org/10.1056/NEJMoa1109016]
Wiestner, A., Rosenwald, A., Barry, T. S., Wright, G., Davis, R. E., Henrickson, S. E., Zhao, H., Ibbotson, R. E., Orchard, J. A., Davis, Z., Stetler-Stevenson, M., Raffeld, M., Arthur, D. C., Marti, G. E., Wilson, W. H., Hamblin, T. J., Oscier, D. G., Staudt, L. M. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 101: 4944-4951, 2003. [PubMed: 12595313] [Full Text: https://doi.org/10.1182/blood-2002-10-3306]
Wiley, J. S., Dao-Ung, L. P., Gu, B. J., Sluyter, R., Shemon, A. N., Li, C., Taper, J., Gallo, J., Manoharan, A. A loss-of-function polymorphic mutation in the cytolytic P2X7 receptor gene and chronic lymphocyte leukaemia: a molecular study. Lancet 359: 1114-1119, 2002. [PubMed: 11943260] [Full Text: https://doi.org/10.1016/S0140-6736(02)08156-4]
Wisniewski, D., Weinreich, J. Lymphatische Leukaemie bei Vater und Sohn. Blut 12: 241-244, 1966. [PubMed: 5951952] [Full Text: https://doi.org/10.1007/BF01632449]