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 ... 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 ... 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.
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 ... 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). - 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 dbSNP 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.
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.