B‐cell monoclonal lymphocytosis and B‐cell abnormalities in the setting of familial B‐cell chronic lymphocytic leukemia

Abstract

Background: Among all hematologic malignancies, B-cell chronic lymphocytic leukemia (BCLL) has the highest familial clustering (three-to sevenfold increase), strongly suggesting a genetic component to its etiology. Familial BCLL can be used as a model to study the early pathogenesis of this disease.Methods: We examined nine kindreds from the National Cancer Institute's Familial BCLL Registry, consisting of 19 affected members with BCLL and 33 clinically unaffected first-degree relatives. Flow cytometric immunophenotyping to detect a B-cell monoclonal lymphocytosis (BCML) was performed. Monoclonality was confirmed by polymerase chain reaction analysis of whole blood DNA. Cell cycle analysis for aneuploidy was conducted.Results: In all affected individuals, we observed the classic BCLL CD5/CD19/CD20/CD23 immunophenotypic patterns. Six of the 33 unaffected individuals (18%) had evidence of BCML. Additional individuals (13/33, 39%) showed some other abnormality, whereas 14 individuals (42%) were normal. Based on an estimated prevalence of 0.7% for BCML in the general population, the finding of six subjects (18%) with clonal abnormalities in this relatively modest sample was significantly greater than expected (i.e., 18% vs. 0.7%, P < 5.7 ؋ 10

Genetically identical twin transplantation for chronic lymphocytic leukemia

“…22 Two studies report the increased existence of monoclonal B-cell lymphocytosis (MBL) in unaffected firstdegree relatives of persons with familial CLL. The 15-18% 23,24 prevalence of MBL in this setting contrasts with a 0.1-5% prevalence in normals. 25,26 Whether MBL is a precursor state to CLL or other lymphoproliferative disorders is unknown.…”

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

“…Looking differentially at the CD19 dim and CD19 bright subsets led to the recognition of this subset: CD19 dim, CD20 þ , CD5À, CD23À, kappa restricted, IgD dim, IgM þ , CD27 þ /dim, CD38 þ and CD69 þ . In a previous report 4 , this individual had a small cluster of kappabearing cells, and single-cell PCR confirmed the presence of a single clone (unpublished observation).…”

“…A monoclonal B-cell lymphocytosis (MBL) could represent, in a proportion of cases, an early stage of CLL, [1][2][3] and an increased prevalence of MBL in first-degree relatives (FDR) of familial CLL compared to the general population has been reported. 4,5 In order to study MBL as the early precursor of CLL, we investigated peripheral blood from the unaffected FDR of familial CLL, using high-sensitivity, multicolor flow cytometry (MCFCM) techniques, that is, sevencolor, nine parameters.…”

Hematopoietic stem cell aging and chronic lymphocytic leukemia pathogenesis

“…The prevalence of MBL is known to increase with age [18,19]. The reported MBL prevalence ranges from \1 % [62,63] to 18 % [64], depending on the evaluated populations and the detection methods. Most MBL clones exhibit an immunophenotype similar to that of CLL [65], and CLL requiring treatment develops in subjects with CLL-like phenotypes and lymphocytosis at an annual rate of 1.1-1.4 % [18,66].…”