Surface IgM expression and function are associated with clinical behavior, genetic abnormalities, and DNA methylation in CLL

Abstract

Key Points• High sIgM level is a potential key factor associated with poorer clinical outcome in CLL.• Genetic and epigenetic features influence sIgM levels and function in CLL.Chronic lymphocytic leukemia (CLL) with unmutated (U-CLL) or mutated (M-CLL) immunoglobulin gene heavy-chain variable region (IGHV) displays different states of anergy, indicated by reduced surface immunoglobulin M (sIgM) levels and signaling, consequent to chronic (super)antigen exposure. The subsets also differ in the incidence of high-risk genetic aberrations and in DNA methylation profile, preserved from the maturational status of the original cell. We focused on sIgM expression and function, measured as intracellular Ca 21 mobilization following stimulation, and probed correlations with clinical outcome. The relationship with genetic features and maturation status defined by DNA methylation of an 18-gene panel signature was then investigated. sIgM levels/signaling were higher and less variable in U-CLL than in M-CLL and correlated with disease progression between and within U-CLL and M-CLL. In U-CLL, increased levels/signaling associated with 112, del(17p) or NOTCH1 mutations. In M-CLL, there were fewer genetic lesions, although the methylation maturation status, generally higher than in U-CLL, varied and was increased in cases with lower sIgM levels/signaling. These features revealed heterogeneity in M-CLL and U-CLL with clear clinical correlations. Multivariate analyses with phenotype, genetic lesions, or DNA methylation maturation status identified high sIgM levels as a new potential independent factor for disease progression. Multiple influences on sIgM include the cell of origin, the clonal history of antigen encounter in vivo, and genetic damage. This simple marker compiles these different factors into an indicator worthy of further investigations for prediction of clinical behavior, particularly within the heterogeneous M-CLL subset. (Blood. 2016;128(6):816-826)

Chronic lymphocytic leukaemia genomics and the precision medicine era

“…IGHV ‐mutated CLL belonged to the high‐programmed DNA methylation subtype and the intermediate‐programmed cases were enriched in CLL using IGHV3‐21 . Furthermore, DNA methylation maturation status inversely associates with surface IgM levels and BCR signalling capacity in mutated CLL (D'Avola et al , ). Surface IgM levels and signalling were higher in unmutated CLL than in mutated CLL and correlated with disease progression.…”

“…The signalling couple, CCR7 and CCL19 has been associated with central nervous system localization on NOTCH1-mutated T-ALL samples (Buonamici et al, 2009). NOTCH1 mutations are enriched in CLL harbouring trisomy 12 (Balatti et al, 2012;Puente et al, 2015) and are significantly more common in CLL with unmutated IGHV genes, when they are associated with increased levels and signalling of surface IgM (D'Avola et al, 2016). Mutations in the FBXW7 and MED12 genes might also deregulate the NOTCH1 signalling pathway in CLL.…”

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

“…The circulating CLL cells from both subsets are characterized by low but variable surface IgM (sIgM) levels and signaling capacity (17). Although sIgM levels and signaling capacity are typically higher in U-CLL than in M-CLL (17)(18)(19), variability is evident in both subsets (17).…”

The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia

“…Interestingly, cerdulatinib also induced greater levels of cell death in samples expressing higher levels of sIgM (MFI >50) (Figure 4G). Therefore cerdulatinib may achieve superior responses in samples with a greater signalling capacity, since sIgM expression correlates with the ability of the CLL cell to flux calcium(35). …”