Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia

Abstract

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

“…This might be analogous to the decreased Syk expression that is observed upon T cell maturation [38]. While we have not assessed the activity of ZAP-70 in these cells, ZAP-70 has clearly been shown to be phosphorylated in B cell lines and to be functional in pro-B cells [23,34]. Given the modest defect in H chain allelic exclusion in the absence of Syk, it is interesting to speculate that the apparently greater dependence of L chain isotype exclusion on Syk is a reflection of the decreased expression of ZAP-70 in immature B cells.…”

“…ZAP-70 had initially thought not to be expressed by B cells [9]. However, ZAP-70 has recently been shown to be expressed in B cells from a subgroup of patients with chronic lymphocytic leukemia [34,35], and by pro-, pre-, and mature B cells of the mouse [23]. To establish whether ZAP-70 was expressed in immature B cells we immunoblotted whole-cell lysates from cultured immature B cells with antibody to ZAP-70.…”

Frequency analysis of HLA class I alleles in Iranian patients with progressive and non-progressive chronic lymphocytic leukemia

“…Patients with CLL are classified into IGHV mutated and unmutated subtypes based on the mutational status of the IGHV genes of the leukemic B-cells [11]. These two different subtypes of patients have different molecular and clinical features, in terms of CD38 and ZAP-70 expression and disease progression [31,32]. CLL patients with mutated IGHV genes tend to express lower levels of CD38 and ZAP-70 molecules with a milder disease, as compared to patients with unmutated IGHV genes [12,13,30].…”

Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma

“…20 Since somatic hypermutation is a hallmark of B cells which have passed through the germinal center, some investigators have postulated that CLL/SLL associated with unmutated IgV genes is derived from naïve, pre germinal B cells and that CLL/SLL with mutated IgV genes is derived from post germinal B cells. 11,[21][22][23] Since patients with unmutated IgV genes are reported to have a significantly worse prognosis, 11 reliable and easier methods to differentiate these groups at early stages of disease would be clinically valuable. ZAP-70 assessment in routinely processed tissue, in our experience, is a convenient alternative to sequencing.…”