title: The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop.
abstract: The c-Myc oncoprotein regulates >15% of the human transcriptome and a limited number of microRNAs (miRNAs). Here, we establish that in a human B-lymphoid cell line, Myc-repressed, but not Myc-stimulated, genes are significantly enriched for predicted binding sites of Myc-regulated miRNAs, primarily those comprising the Myc-activated miR-17~92 cluster. Notably, gene set enrichment analysis demonstrates that miR-17∼92 is a major regulator of B-cell receptor (BCR) pathway components. Many of them are immunoreceptor tyrosine inhibitory motif (ITIM)-containing proteins, and ITIM proteins CD22 and FCGR2B were found to be direct targets of miR-17∼92. Consistent with the propensity of ITIM proteins to recruit phosphatases, either MYC or miR-17~92 expression was necessary to sustain phosphorylation of spleen tyrosine kinase (SYK) and the B-cell linker protein (BLNK) upon ligation of the BCR. Further downstream, stimulation of the BCR response by miR-17-92 resulted in the enhanced calcium flux and elevated levels of Myc itself. Notably, inhibition of the miR-17~92 cluster in diffuse large B-cell lymphoma (DLBCL) cell lines diminished the BCR response as measured by SYK and BLNK phosphorylation. Conversely, human DLBCLs of the BCR subtype express higher Myc and mir17hg transcript levels than other subtypes. Hence, the Myc-miR-17-92-BCR axis, frequently affected by genomic rearrangements, constitutes a novel lymphomagenic feed-forward loop.
authors.affiliation: Division of Cancer Pathobiology/Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: James N
authors.initials: JN
authors.lastname: Psathas
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Doonan
authors.forename: Pichai
authors.initials: P
authors.lastname: Raman
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Freedman
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Minn
authors.forename: Andrei
authors.initials: A
authors.lastname: Thomas-Tikhonenko
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C447641:BANK1 protein, human; C497867:CD22 protein, human; C499173:FCGR2B protein, human; C423544:FCRL4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C568997:MIR17HG, human; C489427:MYC protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D011961:Receptors, Fc; D017452:Receptors, IgG; D051918:Sialic Acid Binding Ig-like Lectin 2; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D002118:Calcium