miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1.
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.
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA; Central European Institute of Technology, Masaryk University, Brno, Czech Republic; and Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.
Marek
M
Mraz
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Liguang
L
Chen
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Laura Z
LZ
Rassenti
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Emanuela M
EM
Ghia
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Hongying
H
Li
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Kristen
K
Jepsen
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Erin N
EN
Smith
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Karen
K
Messer
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Kelly A
KA
Frazer
University of California-San Diego, Moores Cancer Center, Department of Medicine, La Jolla, CA;
Thomas J
TJ
Kipps
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000368:Aged; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell; D012097:Repressor Proteins; C486626:FOXP1 protein, human; C098587:GAB1 protein, human; C533097:MIR150, human