miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1

Abstract

Key Points• The most abundant miRNA in CLL, miR-150, is expressed at lower levels in cases with unfavorable clinicobiological markers and worse prognosis.• miR-150 regulates expression of genes encoding proteins that modulate BCR signaling in CLL.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 z-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, 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 genes. 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 39 untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/ survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. 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, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome. (Blood. 2014;124(1):84-95)

Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

“…Here, we confirmed that miR-150 is overexpressed in CLL cells and serum compared with healthy controls, as was previously reported by Mraz et al (17) (for its cellular expression) and by Moussay et al (14) (for its extracellular plasma expression). MicroRNA-150 deregulation has been reported in various cancers, including cutaneous T-cell lymphoma (28) and Burkitt lymphoma (29), as well as in solid cancers, such as in esophagi squamous carcinoma (30), non-small-cell lung carcinoma (31) and colorectal cancer (32).…”

“…In addition, this downregulation was reported in the proliferation center of CLL lymph nodes (18). Recently, it was demonstrated that miR-150 could affect BCR signaling and that a lower expression of miR-150 was found in IgM responder patients (17). All of these data taken together indicate that miR-150 may be a potential tumor suppressor and that its downregulation is associated with a better response to mi- (E) Serum miR-150 level was compared in paired samples from the same patients at diagnosis and after molecular remission (n = 7).…”

“…The aim of the present study was to evaluate the clinical value of cellular and serum miR-150 because this microRNA is the most abundant microRNA in CLL cells (17) and because its plasma form has been suggested as a biomarker in CLL (14).…”

“…This microRNA plays an important role in normal and malignant hematopoiesis (15). In addition, plasma (14) and cellular (16,17) microRNA-150 were both downregulated in poor prognosis CLL patients based on ZAP70 and IgHV mutational status. A low level of cellular microRNA-150 was also observed in CLL proliferation centers (18), and microRNA-150 is differentially expressed according to the stereotyped B-cell receptor (BCR) subset taken into consideration (19), emphasizing its pivotal role in CLL.…”

“…A low level of cellular microRNA-150 was also observed in CLL proliferation centers (18), and microRNA-150 is differentially expressed according to the stereotyped B-cell receptor (BCR) subset taken into consideration (19), emphasizing its pivotal role in CLL. Finally, a recent study showed that microRNA-150 was the most abundant microRNA in CLL cells and that it can contribute to the proficiency of BCR signaling (17).…”