title: CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia.
abstract: We examined the role of microRNAs (miRNAs) in targeting the stromal-derived factor 1α/CXCR4 (SDF-1α/CXCR4) axis to overcome chemoresistance of AML cells. Microarray analysis of OCI-AML3 cells revealed that the miRNA let-7a was downregulated by SDF-1α-mediated CXCR4 activation and increased by CXCR4 inhibition. Overexpression of let-7a in AML cell lines was associated with decreased c-Myc and BCL-XL protein expression and enhanced chemosensitivity, both in vitro and in vivo. We identified the transcription factor Yin Yang 1 (YY1) as a link between SDF-1α/CXCR4 signaling and let-7a, as YY1 was upregulated by SDF-1α and downregulated by treatment with a CXCR4 antagonist. ChIP assay confirmed the binding of YY1 to unprocessed let-7a DNA fragments, and treatment with YY1 shRNA increased let-7a expression. In primary human AML samples, high CXCR4 expression was associated with low let-7a levels. Xenografts of primary human AML cells engineered to overexpress let-7a exhibited enhanced sensitivity to cytarabine, resulting in greatly extended survival of immunodeficient mice. Based on these data, we propose that CXCR4 induces chemoresistance by downregulating let-7a to promote YY1-mediated transcriptional activation of MYC and BCLXL in AML cells.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jacamo
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Carlo
authors.initials: C
authors.lastname: Croce
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000502:physiology; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D059467:Transcriptome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D050986:YY1 Transcription Factor / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C494811:BCL2L1 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D035683:MicroRNAs; D019718:Receptors, CXCR4; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D051020:bcl-X Protein; C487931:mirnlet7 microRNA, human; D003561:Cytarabine