Excessive antigen reactivity may underlie the clinical aggressiveness of chronic lymphocytic leukemia stereotyped subset #8

Abstract

Key Points• mAbs from aggressive CLL subset #8 display extreme antigen polyreactivity, in clear contrast with the mAbs from other aggressive CLL subsets.• Subset #8 CLL clones respond avidly to stimulation by multiple antigens and this may underlie their noted propensity to transform.Subset #8 is a distinctive subset of patients with chronic lymphocytic leukemia (CLL) defined by the expression of stereotyped IGHV4-39/IGKV1(D)-39 B-cell receptors. Subset #8 patients experience aggressive disease and exhibit the highest risk for Richter transformation among all CLL. In order to obtain biological insight into this behavior, we profiled the antigen reactivity and signaling capacity of subset #8 vs other clinically aggressive stereotyped subsets, namely subsets #1 and #2. Twenty-seven monoclonal antibodies (mAbs) from subsets #1, #2, and #8 CLL clones were prepared as recombinant human immunoglobulin G1 and used as primary antibodies in enzyme-linked immunosorbent assays against representatives of the major classes of established antigenic targets for CLL. Subset #8 CLL mAbs exhibited broad polyreactivity as they bound to all antigens tested, in clear contrast with the mAbs from the other subsets. Antigen challenge of primary CLL cells indicated that the promiscuous antigen-binding activity of subset #8 mAbs could lead to significant cell activation, again in contrast to the less responsive CLL cells from subsets #1 and #2. These features constitute a distinctive profile for CLL subset #8, supporting the existence of distinct mechanisms of aggressiveness in different immunogenetic subsets of CLL. (Blood. 2015;125(23):3580-3587)

Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment

“…IgD stimulation can cause CLL-cell apoptosis [125] or survival and plasma cell differentiation [126] and differential responsiveness to IgD stimulation has been linked to clinical outcome [127]. Although the nature of the antigens stimulating CLL-BCRs in patients is still poorly defined, some reports have shown that U-CLL BCRs are polyreactive and mostly recognize autoantigens and other environmental antigens [40, 128–137] including cytoskeletal non-muscle myosin heavy chain IIA (MYHIIA), vimentin, cofilin-1, Fc tail of IgG, single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), lipopolysaccharide (LPS), apoptotic cells, oxidized low-density lipoprotein (ox-LDL), lupus-associated ribonuclear protein Smith (Sm), human immunodeficiency virus 1 and hepatitis C viral antigens and bacterial antigens (Figure 3). In contrast, affinity-matured BCRs from M-CLL cases bind to a restricted set of more specific antigens, including β-(1,6)-glucans from yeast and fungi [138] and the Fc tails of rheumatoid factors [131–133, 139] (Figure 3).…”

“…U-CLL cells express BCRs specific for autoantigens, including non-muscle myosin heavy chain IIA (MYHIIA), vimentin, lupus associated ribonuclear protein Smith (Sm), single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), oxidized low-density lipoprotein (oxLDL) as well as microbial antigens, including lipo-polysaccaride (LPS) [40, 128–137]. U-CLL are generally highly responsive to antigenic stimulation [10, 120], as well as those expressing high levels of CD38 [10, 117] and ZAP70 [119].…”

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

“…10,[15][16][17][18][19][20][21][22][23][24][25] In addition, preliminary observations in CLL, in relatively small patient series, suggest that the frequency and patterns of mutations within several genes, namely, NOTCH1, SF3B1 and TP53, may differ amongst subsets of patients carrying stereotyped BcRs, the paradigmatic example being the recently observed enrichment of SF3B1 mutations in the clinically aggressive subset #2. [26][27][28] With this in mind, we sought to systematically evaluate the mutational status of BIRC3, MYD88, NOTCH1, SF3B1 and TP53 in 565 CLL patients assigned to one of 10 major stereotyped subsets, and representing cases with varying SHM status, i.e.…”

Problems of Cancer Treatment. Part I. Theory of Treatment Based on Known Mechanisms of Anticancer Immunological Responses

“…Blood supply of neoplastic tumour condition inflow of glucose to cancer cells usually manifesting glycolytic metabolism [41], which represents an important stage in further development on the lesion. This results in a more rapid growth of the tumour and in presence of accompanying cells of chronic inflammatory process, macrophages and lymphocytes.…”