Familial Aspects of Chronic Lymphocytic Leukemia, Monoclonal B-Cell Lymphocytosis (MBL), and Related Lymphomas

Abstract

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 epidemiological studies have been generally inconsistent inconsistent and well-defined extrinsic risk factors are unknown. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions including non-Hodgkin lymphomas, especially other indolent lymphomas. The precursor condition, monoclonal B-cell lymphocytosis (MBL) also aggregates in CLL families. However because the baseline population risks for CLL and other indolent lymphomas are low, the absolute risk to a first-degree relative for developing CLL or a related disease is also low. 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 several genes as being important in CLL but more studies are needed to verify these findings. Results from whole genome association are promising. 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.

Figure 1

Pedigree with multiple cases of CLL and other LPD

Figure 2

Pedigree with both CLL and WM cases, as well as the precursor MGUS.

Figure 3

Six-Color Flow-Cytometric Analysis, Showing Representative Kappa Light-Chain Restriction in Prediagnostic Blood Samples from the Patients. (Reprinted from Landgren et al,36) Panel A shows a bivariant plot of CD45 against side scatter, showing the isolation of lymphocytes incubated with anti-CD45 allophycocyanin H7 (APC-H7). Panel B shows a plot of CD19 against CD5. The monoclonal B-cell lymphocytosis (MBL) clone (red), positive for anti-CD19 peridinin–chlorophyll–protein cyanine 5.5 (PerCP-Cy5.5), shows coexpression of CD19 and CD5. The green population represents the remaining CD5-positive T cells, and the blue population represents the remaining polyclonal B cells. Panel C shows that the red population, positive for anti-kappa allophycocyanin (APC), has a kappa light-chain restriction. Panel D shows that the remaining B cells (blue) are polyclonal. FITC denotes fluorescein isothiocyanate, and PE phycoerythrin.