Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL

Abstract

Key Points• Low-count and high-count monoclonal B-cell lymphocytosis (MBL) have distinct immunogenetic signatures, with only the latter resembling CLL.• Rather than a true premalignant condition, low-count MBL may merely reflect immune senescence or result from persistent antigen stimulation.Chronic lymphocytic leukemia (CLL) -like monoclonal B-cell lymphocytosis (MBL) shares common immunophenotype and cytogenetic abnormalities with CLL, from which it is discriminated by a cutoff value of 5 3 10 9 /L circulating clonal B cells. However, the clonal size in MBL is extremely variable and allows discrimination of two distinct entities (highcount [HC] and low-count [LC]-MBL) based on a cutoff value of 0.5 3 10 9 /L clonal B cells. HC-MBL is associated with lymphocytosis and progresses to CLL requiring treatment at a rate of 1.1% per year, whereas LC-MBL is found in the general population only through high-sensitivity techniques and carries limited, if any, risk of progression. We performed an immunogenetic profiling of 333 cases with CLL-like MBL supplemented by detailed comparisons with CLL, focusing especially on CLL Rai stage 0 (CLL-0). LC-and HC-MBL had similar somatic hypermutation status, yet different IGHV gene repertoires and frequencies of B-cell receptor (BcR) stereotypy. In particular, stereotyped BcRs were infrequent in LC-MBL and were often not CLL specific. In contrast, HC-MBL exhibited clear immunogenetic similarities to CLL-0. These findings indicate that LC-MBL may not represent a true preleukemic condition, thus differing from HC-MBL/CLL-0 in which the identification of factors endowing malignant potential is strongly warranted. (Blood. 2013; 121(22):4521-4528)

Subjects with chronic lymphocytic leukaemia‐like B‐cell clones with stereotyped B‐cell receptors frequently show MDS‐associated phenotypes on myeloid cells

“…This might occur in an antigen-independent way as early as at the HSC level, as recently proposed by Kikushige et al (2011). Therefore, these early expansions would more likely translate into an oligoclonal MBL lo stable condition, in which clonality will not directly translate into malignancy (Henriques et al, 2013;Vardi et al, 2013); further clonal B-cell expansion might depend on additional micro-environmental factors (e.g. infections) (Casabonne et al, 2012) and/or acquisition of specific (additional) genetic changes by the expanded B-cells (Henriques et al, 2013).…”

“…Biassed usage of specific IGHV genes in both CLL and MBL (Henriques et al, 2013;Vardi et al, 2013) would further support the existence of selective pressurese.g. inherited genetic predisposition factors and/or still unidentified pathogen(s) -that may favour the expansion of specific IGHV-IGHD-IGHJ clones, not only at the B-lymphocyte stage but potentially also at the haematopoeitic stem cell (HSC) compartment (Alizadeh & Majeti, 2011).…”

Immunogenetic Studies of Chronic Lymphocytic Leukemia: Revelations and Speculations about Ontogeny and Clinical Evolution

“…LC-MBL increases with age, being present in 75% of individuals older than 90 years of age, seems to remain stable over time, and exhibits an immunogenetic signature that is distinct from CLL, more similar to the IG gene usage within the elderly. Together with the paucity of CLL-specific BcR IG stereotypy in LC-MBL, this justifies the interpretation of LC-MBL as a manifestation of immune senescence leading to immune restriction likely due to chronic antigenic stimulation (46). Therefore, one might speculate that the "CLL-type" cytogenetic abnormalities of LC-MBL may be acquired during lymphocyte development and maturation, perhaps in conjunction with a particular type of antigenic triggering, and associate Here, however, we propose a possible continuum of events that transit this progenitor cell through distinct clonal conditions and may eventually lead to true malignant transformation.…”

Clonal B-cell lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin: is this a distinct entity?

“…6 MBL was subclassified into a CD5 1ve, CD23 1ve CLL-like category; a CD5 1ve, CD23 2ve, CD20 bright atypical CLL category; and a CD5 2ve category. 3,4 Many subsequent studies have confirmed the biological similarities between clinical CLL-like MBL and early stage CLL 7 and the low rate of progression to CLL requiring therapy. 8,9 Although the diagnostic criteria for CLL-like clinical MBL have been used to refine the diagnosis of CLL, the cutoff of 5 3 10 9 /L 3,4 clonal B lymphocytes for distinguishing clinical MBL from CLL is arbitrary, lacking clinical and/or biological justification.…”