MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia

Garzon, Ramiro; Volinia, Stefano; Liu, Chang–Gong; Fernandez-Cymering, Cecilia; Palumbo, Tiziana; Pichiorri, Flavia; Fabbri, Muller; Coombes, Kevin R.; Alder, Hansjüerg; Nakamura, Tatsuya; Flomenberg, Neal; Marcucci, Guido; Calin, George A.; Kornblau, Steven M.; Kantarjian, Hagop M.; Bloomfield, Clara D.; Andreeff, Michael; Croce, Carlo M.

doi:10.1182/blood-2007-07-098749

Cited by 567 publications

(531 citation statements)

References 36 publications

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“…Total RNA was extracted with miRNeasy Mini Kit (Qiagen) according to the manufacturer's protocol. RNA was labeled and hybridized on miRNA microarray chips as previously described (51). Microarray data have been deposited in GEO (accession no.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia

Chen¹,

Jácamo²,

Konopleva³

et al. 2013

J. Clin. Invest.

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168

130

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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.

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Section: Discussionmentioning

confidence: 99%

CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia

Chen¹,

Jácamo²,

Konopleva³

et al. 2013

J. Clin. Invest.

Self Cite

168

130

View full text Add to dashboard Cite

show abstract

“…These studies showed that leukemic cells of acute leukemia patients have different miRNA expression patterns than normal hematopoietic cells. [18][19][20][21] Quantitative analysis of 397 miRNAs revealed that leukemic cells of pediatric precursor B-ALL patients have different miRNA expression profiles than samples of normal bone marrow and CD34 þ sorted cells. 22 Moreover, miRNAs were significantly differentially expressed between T-ALL cases and normal thymocytes.…”

Section: Aberrant Mirna Expression Characterizes Different Cytogenetimentioning

confidence: 99%

MicroRNAs in acute leukemia: from biological players to clinical contributors

2011

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MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia-silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia.

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“…Up-regulation of miR-191 has also been detected in breast cancer (19). In acute myeloid leukemia (AML), patients with high expression of miR-191 have significantly worse overall and event-free survival than AML patients with low expression (20). Furthermore, PLCD1 and RNF139, two predicted candidate target genes of miR-191, are tumor suppressors in esophageal squamous cell carcinoma and human hereditary kidney cancer, respectively (21,22).…”

Section: Discussionmentioning

confidence: 97%

5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro

Bai¹

2009

Oncol Rep

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Abstract. MicroRNAs (miRNAs) have recently taken center stage in the field of human molecular oncology. Most of the chemotherapeutics are able to interfere with nucleic acid metabolism and gene expression. The purpose of this study was to determine how 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) modify the expression profiles of miRNAs in HCT-8 and HCT-116 colon cancer cells and whether the pharmacodynamic mechanisms of the chemotherapeutics could rely in part on their influence on miRNA expression. The expression profiles of miRNAs were determined using a miRNA microarray containing 856 human miRNA probes. The expression of selected miRNAs was then validated by real-time RT-PCR. Fifty-six up-and 50 down-regulations of miRNA expression with statistical significance were identified in colon cancer cells following exposure to 5-FU or L-OHP compared to matched control cells. The down-regulations of miR-197, miR-191, miR-92a, miR-93, miR-222 and miR-1826, whose expression was significantly down-regulated in both cell lines after the treatment of one drug or in one cell line following exposure to either drug, were further validated. Analysis of the relevant literature indicated that, in line with the tumor suppressive activity of 5-FU and L-OHP, the six down-regulated miRNAs might function as oncogenes due to their overexpression in cancers, and some of them correlated with the poor prognosis and treatment-resistance of cancer. In conclusion, we identify the modification of miRNA expression profiles in colon cancer cells following exposure to 5-FU and L-OHP, and our results indicate that their pharmacodynamic mechanisms could rely in part on their influence on the down-regulated miRNA expression.Further studies are needed to determine whether these miRNAs and their target genes might potentially provide for novel molecular markers and act as novel targets for treatment by interference.

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MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia

Cited by 567 publications

References 36 publications

CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia

CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia

MicroRNAs in acute leukemia: from biological players to clinical contributors

5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro

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