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

• Published in: Blood 2014-07, Vol.124 (1), p.84-95
• Main Authors: Mraz, Marek, Chen, Liguang, Rassenti, Laura Z., Ghia, Emanuela M., Li, Hongying, Jepsen, Kristen, Smith, Erin N., Messer, Karen, Frazer, Kelly A., Kipps, Thomas J.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - biosynthesis; Adaptor Proteins, Signal Transducing - genetics; Adult; Aged; Female; Forkhead Transcription Factors - biosynthesis; Forkhead Transcription Factors - genetics; Gene Expression Regulation, Leukemic - genetics; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Lymphoid Neoplasia; Male; MicroRNAs - genetics; Middle Aged; Oligonucleotide Array Sequence Analysis; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - metabolism; Repressor Proteins - biosynthesis; Repressor Proteins - genetics; RNA, Small Interfering; Signal Transduction - physiology; Transfection
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-09-527234

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 ζ-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 3′ 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. •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.