Abstract
In chronic lymphocytic leukemia (CLL), patients with unmutated immunoglobulin heavy chain variable region gene (UM-CLL) have worse outcomes than mutated CLL (M-CLL) following chemotherapy or chemoimmunotherapy. However, in the era of BCR-targeted therapies, the adverse prognostic impact of unmutated IGHV seems to be diminishing, and there are clinical datasets showing unexpected improved responses in UM-CLL. We investigated the biological differences of BTK activity between these subgroups and further compared the impact of ibrutinib on molecular and cellular behaviors. Immunoblotting analysis revealed that phosphorylated active BTK is significantly higher in UM-CLL. Moreover, UM-CLL, compared to M-CLL, displayed a much higher proliferative capacity that was correlated with higher phospho-BTK and greater sensitivity to ibrutinib. In addition, BTK depletion with siRNA led to a more prominent reduction in the proliferation of UM-CLL, suggesting that elevated BTK activity is responsible for increased cell proliferation. Further, cell signaling activity by multiple measurements was consistently higher in UM-CLL accompanied by a higher sensitivity to ibrutinib. These studies link UM-CLL to elevated BCR signaling, heightened BTK-dependent cell proliferation and increased sensitivity to ibrutinib. The prognostic significance of IGHV mutation should be reevaluated in the era of new therapies targeting BCR signaling.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries and is characterized by the accumulation of CD5+ monoclonal B cells in peripheral blood and secondary lymphoid tissues
The morphology and immunophenotypical features are shared among CLL tumor cells, the clinical course of the disease varies from indolent to aggressive related to a variety of established prognostic factors such as age, Rai stage, chromosomal abnormalities, mutational status of the immunoglobulin heavy chain gene variable region (IGHV), ZAP70 and CD38 expression [1]
Based on our previous observation that the active phosphorylated form of BTK (Y223), but not total BTK, was significantly higher in CLL B-cells than in normal B cells [9], we conjectured that greater BTK activity may underlie the better clinical responses of UM-CLL subgroup to ibrutinib
Summary
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries and is characterized by the accumulation of CD5+ monoclonal B cells in peripheral blood and secondary lymphoid tissues. The morphology and immunophenotypical features are shared among CLL tumor cells, the clinical course of the disease varies from indolent to aggressive related to a variety of established prognostic factors such as age, Rai stage, chromosomal abnormalities, mutational status of the immunoglobulin heavy chain gene variable region (IGHV), ZAP70 and CD38 expression [1]. Patients with unmutated IGHV, in general, have a more aggressive disease course requiring earlier therapeutic intervention while those with mutated IGHV have much slower disease progression [2, 3]. The median overall survival for early stage patients with unmutated IGHV is 12.6 years as opposed to 23.3 years in those with mutated IGHV [4]. IGHV mutation status is a clinically relevant prognostic marker in CLL
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