Familial Chronic Lymphocytic Leukemia Research Articles

Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through analysis of IgVH gene usage and mutation status in familial CLL

AbstractTo address the proposition that familial B-cell chronic lymphocytic leukemia (CLL) may exhibit a more restricted phenotype than sporadic CLL with respect to immunoglobulin gene usage or ontogenic development, we compared immunoglobulin (Ig) heavy chain variable region (VH) gene usage and IgVH mutation status in 327 patients with CLL from 214 families with 724 patients with sporadic cases. The frequency of mutated CLL was higher in familial CLL (P < .001), and there was evidence of intrafamilial concordance in mutation status (P < .001). The repertoire and frequency of IgVH usage was, however, not significantly different between familial and sporadic CLL. Furthermore, IgVH usage was not correlated between affected members of the same family. These observations provide evidence that familial CLL is essentially indistinguishable from sporadic CLL, favoring a genetic basis to disease development in general rather than a simple environmental etiology.

Immunophenotypic features distinguishing familial chronic lymphocytic leukemia from sporadic chronic lymphocytic leukemia

Familial chronic lymphocytic leukemia (CLL) has the most frequent familial aggregation among hematological malignancies. Familial CLL families have been studied to identify susceptibility genes and other factors that contribute in the etiology of CLL. To date no study has been conducted to evaluate and compare patterns of cell surface antigen expression in familial CLL and sporadic CLL. The pattern of cell surface antigen expression was studied in familial and sporadic CLL to determine if unique identifiers of familial CLL could be detected. Survival in familial CLL verses sporadic CLL was compared and the association between prognosis and CD38 expression studied. Familial and sporadic CLL demonstrated the same characteristic immunophenotype (positive for surface immunoglobulin, CD5, CD19, and CD23 with dim CD20, and CD22). CD2 and CD13 expression, however, were more frequent (30% of cases) in familial CLL (P = 0.0003 for CD2, P = 0.006 for CD13) than in sporadic CLL (2-6%). There was no significant difference in survival in the two groups studied. Although the incidence of CD38 expression was similar in familial and sporadic CLL (47% and 44% respectively) the association with prognosis differed. There was a trend to decreased survival in CD38 positive sporadic (P = 0.06) but not familial CLL patients. We conclude that detection of CD2 or CD13 expression in CLL suggests familial CLL and examination of family history for additional affected members is warranted. Furthermore, CD38 expression does not carry the negative prognosis observed in sporadic CLL.

Possible imprinting and microchimerism in chronic lymphocytic leukemia and related lymphoproliferative disorders.

Based on the concept that the tumorogenesis in chronic lymphocytic leukaemia comprises both an initial, inherited mutation and subsequent somatic mutations, the pleiotypic diversity of familial chronic lymphocytic leukaemia and related malignant lymphoproliferative disorders is generally explained by a repertoire of monoallelic polygenes in the initial mutation. Epigenetic genomic imprinting is a likely mechanism behind of the asynchroneous replicating monoallelic polygenes which is discussed in the light of pleiotrophy and birth order effect. Furthermore, it is discussed that one possible mechanism available for the epigenetic transfer of these genes could be the physiological pregnancy-related microchimerism between mother and fetus.

Germline mutations in RAD51, RAD51AP1, RAD51B, RAD51C,RAD51D, RAD52 and RAD54L do not contribute to familial chronic lymphocytic leukemia

While familial predisposition to B-cell chronic lymphocytic leukemia (CLL) is well recognized no gene which when mutated in the germline has been unambiguously shown to confer susceptibility to the disease. An approach based on mutation screening methods targeted to coding regions of candidate genes offers an attractive strategy for the identification of rare disease-causing alleles. The RAD genes participate in the cellular response to DNA double strand breaks, detecting DNA damage, activating cell cycle checkpoints and apoptosis. Defects in members of these genes are linked to increased chromosomal instability and in lymphoma predisposition, thereby representing strong candidate susceptibility genes a priori. To examine this proposition we screened 75 familial CLL probands for germline mutations in this set of genes. No overt pathogenic mutations were identified. These findings indicate that germline mutations in RAD51, RAD51AP1, RAD51L1, RAD51L3, RAD52 and RAD54L are unlikely to be causal of an inherited predisposition to CLL.

Survival Patterns among Chronic Lymphocytic Leukemia and Other Lymphoma Patients with Family History of Lymphoma.

Background. A role for genetic factors in chronic lymphocytic leukemia (CLL) is unequivocal based on evidence from multiply affected families, from case series, twin and case-control studies, and population-based registry studies. Similar characteristics have been observed for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Population-based studies have found CLL, NHL and HL to co-occur in families. A few hospital-based series have explored survival outcomes in familial vs. sporadic CLL patients based on the hypothesis that genetic mechanisms involved in the causation of familial lymphomas might influence survival, however these have been based on small numbers with inconsistent findings. We have conducted a large study in Scandinavia including more than 41,000 lymphoma patients to quantify survival outcomes among familial vs. sporadic patients.Methods. We used the population-based central Cancer and Multigenerational Registries in Sweden and Denmark to identify all CLL (n=7749), NHL (n=25801), and HL (n=7476) patients diagnosed 1958–2001, with linkable first-degree relatives. All relatives were linked with the Cancer Registries to obtain information on CLL, NHL, and HL. Using Cox proportional hazard models, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of overall survival for CLL, NHL, and HL patients with vs. without family history of lymphoma.Results. We found 85 (1.1%) CLL, 207 (0.8%) NHL, and 96 (1.3%) HL patients with family history of lymphoma. Overall survival was similar for CLL (HR=1.24, 95% CI 0.93–1.67), NHL (HR=0.97, 95% CI 0.80–1.16), and HL (HR=0.78, 95% CI 0.51–1.19) patients with vs. without family history of lymphoma. Risk-estimates were similar when we calculated overall survival by age at lymphoma diagnosis (above vs. below median age), year at diagnosis (before vs. after 1987), and by sex. Consistent with the literature, including all CLL, NHL and HL patients, older age (p<0.001) and male gender (p<0.001) was associated with poorer survival. However, when analyses were restricted to patients with family history of lymphoma, only older age (p<0.005) remained significant.Conclusions: Survival patterns were similar for CLL, NHL, and HL patients with vs. without family history of lymphoma, suggesting that familial lymphomas do not have an altered clinical course. Overall, there is no evidence at this time to modify therapeutic strategies for patients with CLL, NHL, or HL based solely on family history.

Murine models of chronic lymphocytic leukaemia: role of microRNA-16 in the New Zealand Black mouse model.

Mouse models are valuable tools in the study of human chronic lymphocytic leukaemia (CLL). The New Zealand Black (NZB) strain is a naturally occurring model of late-onset CLL characterized by B-cell hyperproliferation and autoimmunity early in life, followed by progression to CLL. Other genetically engineered models of CLL that have been developed include (NZB x NZW) F1 mice engineered to express IL5, mice expressing human TCL1A, and mice overexpressing both BCL2 and a tumour necrosis factor receptor-associated factor. The applicability to human CLL varies with each model, suggesting that CLL is a multifactorial disease. Our work with the de novo NZB model has revealed many similarities to the human situation, particularly familial CLL. In NZB, the malignant clones express CD5, zap-70, and have chromosomal instability and germline Ig sequence. We also identified a point mutation in the 3'-flanking sequence of Mirn16-1, which resulted in decreased levels of the microRNA, miR-16 in lymphoid tissue. Exogenous restoration of miR-16 to an NZB malignant B-1 cell line resulted in cell cycle alterations, suggesting that the altered expression of Mirn15a/16-1 is an important molecular lesion in CLL. Future studies utilizing the NZB mouse could ascertain the role of environmental triggers, such as low dose radiation and organic chemicals in the augmentation of a pre-existing propensity to develop CLL.

Family studies in chronic lymphocytic leukaemia and other lymphoproliferative tumours

Families with multiple individuals affected with chronic lymphocytic leukaemia (CLL) and other related B-cell tumours have been described in the literature. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions, including non-Hodgkin and Hodgkin lymphoma. Monoclonal B-cell lymphocytosis also aggregates in CLL families. However, the clinical implication of familial aggregation is minimal given the overall rarity of CLL. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated immune function and other genes but more studies are needed to verify these findings. The ability to conduct large scale genomic studies will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate aetiological pathways.

Overview of monoclonal B‐cell lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) has been the subject of more intensive investigation for the last 10 years. The increased presence of MBL in unaffected, first-degree relatives with familial chronic lymphocytic leukaemia (CLL) suggest that it is surrogate marker for early disease. In normal population studies, MBL is found to be increased in ageing subjects. Consensus criteria for the diagnosis of MBL have been proposed. The differential diagnosis has been further clarified and the prevalence of MBL is most prominent in the elderly. The aetiology of MBL is unknown but probably involves immune mechanism of senescence or altered response. Environmental health studies suggest that exposure to certain toxins may lead to MBL but further work is needed. MBL is a precursor to CLL but may also regress, remain stable or progress to clinical CLL.

B‐cell repertoire and clonal analysis in unaffected first degree relatives in familial chronic lymphocytic leukaemia kindred

Monoclonal B cell lymphocytosis (MBL) was detected in four unaffected first-degree relatives (FDR) in a familial chronic lymphocytic leukaemia (CLL) kindred. The proband remains untreated and two male siblings have died. The four unaffected siblings have been followed for a five-year period. All four FDR developed a kappa(+)CD5(+) MBL detected by flow cytometry. Poymerase chain reaction (PCR) for IGHV rearrangement showed evidence of oligoclonality in three of these individuals. Single cell PCR of flow cytometric sorted kappa(+) cells combined with Ig kappa light chain gene sequencing revealed further evidence of monoclonality in two of these individuals. Three of these individuals all showed evidence of hyper-somatic mutations. The B-cell repertoire in unaffected FDR in familial CLL offers a new area to investigate the interface between the immune system and lymphoid neoplasm.

Molecular profiling of chronic lymphocytic leukaemia: genetics meets epigenetics to identify predisposing genes

Molecular profiling may lead to a better understanding of a disease. This knowledge is especially important in malignancies, where multiple alterations are required during the progression from premalignant to malignant stages. Such information can be useful for the development of novel biomarkers that allow the prediction of a clinical course, response to treatment or early detection. Molecular data is also utilized to develop targeted therapies. Moreover, gene defects identified in profiling studies will help to understand the molecular pathways disrupted in the disease. This review provides an overview of molecular profiling approaches in chronic lymphocytic leukaemia (CLL). We will describe our current understanding of genetic alterations in CLL, the use of familial CLL for the identification of predisposing mutations, and the search for epigenetic alterations in CLL.

Chronic Lymphocytic Leukemia: Keeping Cell Death at Bay

Chronic lymphocytic leukemia (CLL) is a common adult leukemia caused by abnormal accumulation of B cells. Raval et al. (2007) now implicate dowregulation of the expression of the kinase DAPK1 both genetically and epigenetically in familial and sporadic CLL.

Germline mutations in SPI1 and MADD do not contribute to familial chronic lymphocytic leukaemia

Germline mutations in SPI1 and MADD do not contribute to familial chronic lymphocytic leukaemia

No association of ARLTS1 polymorphisms and risk for familial chronic lymphocytic leukaemia

No association of ARLTS1 polymorphisms and risk for familial chronic lymphocytic leukaemia

Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial chronic lymphocytic leukemia

AbstractChronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia in adults in western countries. A genome scan of CLL-prone families revealed a lod score of one in band 13q22.1. To investigate this finding, we selected 6 CLL families consisting of 63 individuals (CLL affected, n = 19; unaffected, n = 44) for fine mapping of a 23-megabase region in 13q14.2-q22.2. Interphase fluorescence in situ hybridization (FISH) revealed 13q14 deletion in 85% (11/13) of CLL patients. Four CLL families shared a 3.68-Mb minimal region in 13q21.33-q22.2. Two asymptomatic siblings who shared the 13q21.33-q22.2 at-risk haplotype exhibited CD5+ monoclonal B-cell lymphocytosis (MBL) on flow cytometry. One of these individuals also had a 13q14 deletion by FISH. These 2 individuals with MBL shared the at-risk haplotype with their CLL-affected relatives, providing further evidence of the relationship between CLL and MBL, as well as of the biologic significance of this novel region. Using direct DNA sequencing analysis, we screened 13 genes for mutations, but no frameshift or nonsense mutations were detected. Our studies revealed that 11 of the 13 genes in the candidate region were expressed in immune tissues, supporting their functional relevance in investigations of familial CLL. In conclusion, we identified a novel candidate region that may predispose to familial CLL.

Familial CLL: Genes and Environment

Families with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome. While some environmental factors (such as farming-related exposures and occupational chemicals) may increase risk of CLL, results of epidemiologic studies have been generally inconsistent. Rates of CLL in the population show significant international variation, with the highest rates in the U.S. and Europe and the lowest rates in Asia. Migrants from Asia to the U.S. also have low rates of CLL, which supports a greater role for genetic compared with environmental risk factors. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions including non-Hodgkin and Hodgkin lymphoma. Monoclonal B-cell lymphocytosis also aggregates in families with CLL. However, the clinical implication of familial aggregation is minimal given the overall rarity of CLL. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility, but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated immune function and other genes, but more studies are needed to verify these findings. The ability to conduct large-scale genomic studies will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate etiologic pathways.

Trinucleotide repeat dynamic mutation identifying susceptibility in familial and sporadic chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) has a strong hereditary component, but an understanding of predisposition genes is poor. Anticipation with familial CLL has been reported, although the molecular mechanism is unknown. Expansion of trinucleotide repeat sequences underlies anticipation observed in neurodegenerative disease. A polymerase chain reaction-based assay was used to analyse the stability of ten CCG- and CAG-trinucleotide repeat tracts in 18 CLL families and 140 patients with the sporadic form of the disease. The study suggests that anticipation, if it occurs in CLL, is not linked to CCG- and CAG-repeat expansion, however, variation in repeat length at certain loci (FRA16A) may permit identification of susceptible family members. In addition, polymorphisms with prognostic significance were identified. These were high length (but not expanded) repeats at FRA11B (P = 0.01), ATXN1 (P = 0.032) and ATXN3 (P = 0.022), all associated with poor risk disease.

Chronic Lymphocytic Leukaemia Has a More Aggressive Phenotype in Asians Compared to Caucasians.

Chronic lymphocytic leukaemia (CLL) is the commonest leukaemia in the western world with an incidence of 3 per 100,000. The precise aetiology remains obscure but there is clear evidence for a genetic predisposition. CLL has a seven-fold increased incidence amongst relatives of index cases compared to controls and the disease is also more common in males. These genetic subgroups can also determine phenotype as familial CLL has a younger age of onset and increased association with second malignancies compared to sporadic cases. Similarly, CLL is more aggressive and more frequently requires treatment in males in comparison to female patients. The incidence of CLL also varies according to racial origin and has been found to be up to 20-fold less common in Japanese and Asian populations compared to Caucasian populations. However, it is not known whether or not there is also phenotypic variation in CLL patients according to racial origin.We studied 29 Asian patients with a diagnosis of CLL and compared disease characteristics with a control group of 277 Caucasians. We found that CLL in Asians was diagnosed at a younger age (median age 62yr in Asians vs 70yr Caucasians, p=0.001) and was also more common in males (M:F Asians 3.1:1; Caucasians 1.3:1, p=0.023). No association was seen between racial origin and either IGVH status or CD38 status.Interestingly, we also found that the Asian population had a more aggressive clinical phenotype as indicated by a shorter time to the requirement of first treatment (TTFT) (p=0.019). This observation was independent of both age and gender. Although no difference was seen in overall survival between the two groups, ‘non-leukaemia related' deaths were more common in the older Caucasian population. 27.5% of Caucasian deaths occurred in patients who had never required treatment for CLL whereas no deaths occurred among untreated Asian patients, for whom the primary cause of death was progressive leukaemia. The failure to observe a difference in overall survival was therefore partly accounted for by an increase in non-leukaemia related deaths in Caucasians.In conclusion, we have shown that there are phenotypic differences in CLL patients according to the racial origin. CLL in Asian patients occurs at a younger age and is associated with a more aggressive phenotype. The mechanisms underlying these observations are unknown but warrant further investigation.

Identification of a new monoclonal B-cell subset in unaffected first-degree relatives in familial chronic lymphocytic leukemia

Identification of a new monoclonal B-cell subset in unaffected first-degree relatives in familial chronic lymphocytic leukemia

Hodgkin's Type of Richter's Syndrome in Familial Chronic Lymphocytic Leukemia Treated with Cladribine and Cyclophosphamide

Second malignancies are frequent complications in patients with chronic lymphocytic leukemia (CLL). Hodgkin's disease (HD) has been observed in approximately 0.5% of the patients with CLL and is known as Hodgkin's type Richter's syndrome (H-RS). We present a 64-year-old male patient with a familial history of CLL who developed H-RS in abdominal lymph nodes 6 years after CLL diagnosis and 18 months after treatment with cladribine (2-CdA) and cyclophosphamide. HD was diagnosed by fine needle aspiration. The disease was refractory to treatment with two courses of CHOP and three courses of ABVD chemotherapy. In the current literature we found case reports of only 6 patients with H-RS who were treated with fludarabine (FA) before transformation, and, to our knowledge the presented patient is the first to develop H-RS after treatment with 2-CdA combined with cyclophosphamide. He is also the first published patient with familial CLL in whom this complication developed.

High occurence of DRB1 11 in chronic lymphocytic leukaemia families.

Recently, linkage analysis of a series of familial chronic lymphocytic leukaemia (CLL) showed that affected sibling pairs did not share common major histocompatibilty complex haplotypes. We analysed Class I and II antigens in 11 Italian families with familial CLL. Although there was no association of disease status with any particular human leucocyte antigen, there was an overrepresentation of DRB1 11 alleles in these families (P = 0.009). A similar trend was also observed in a second series of nine French families (P = 0.002). Larger studies are needed to determine whether non-inherited paternal or maternal DRB1 antigens play a role in familial CLL development.