MicroRNA-150 Contributes to the Proficiency of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia by Regulating Expression of GAB1 and FOXP1 Genes

We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia-cell-expression levels that varied among patients. CLL cells that expressed ZAP-70 or that used unmutated IGHV each had a median expression-level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3 UTRs having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that may enhance B-cell receptor (BCR) signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 levels was a significant independent predictor of longer treatment-free-survival (TFS) or overall survival (OS), whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for OS. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor (BCR), thereby possibly accounting for the noted association of expression of miR-150 and disease outcome.

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Mraz M, Chen L, Rassenti LZ, Ghia EM, Li H, Jepsen K, Smith EN, Messer K, Frazer KA, Kipps TJ