Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia.
Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia.
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DOI：
10.1001/jama.2010.1919
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发表时间：
2011-01-05
影响因子：
120.7
通讯作者：
Croce, Carlo M.
中科院分区：
文献类型：
--
作者：
Fabbri, Muller;Bottoni, Arianna;Shimizu, Masayoshi;Spizzo, Riccardo;Nicoloso, Milena S.;Rossi, Simona;Barbarotto, Elisa;Cimmino, Amelia;Adair, Brett;Wojcik, Sylwia E.;Valeri, Nicola;Calore, Federica;Sampath, Deepa;Fanini, Francesca;Vannini, Ivan;Musuraca, Gerardo;Dell'Aquila, Marie;Alder, Hansjuerg;Davuluri, Ramana V.;Rassenti, Laura Z.;Negrini, Massimo;Nakamura, Tatsuya;Amadori, Dino;Kay, Neil E.;Rai, Kanti R.;Keating, Michael J.;Kipps, Thomas J.;Calin, George A.;Croce, Carlo M.
Chromosomal abnormalities (namely 13q, 17p, and 11q deletions) have prognostic implications and are recurrent in chronic lymphocytic leukemia (CLL), suggesting that they are involved in a common pathogenetic pathway; however, the molecular mechanism through which chromosomal abnormalities affect the pathogenesis and outcome of CLL is unknown. To determine whether the microRNA miR-15a/miR-16-1 cluster (located at 13q), tumor protein p53 (TP53, located at 17p), and miR-34b/miR-34c cluster (located at 11q) are linked in a molecular pathway that explains the pathogenetic and prognostic implications (indolent vs aggressive form) of recurrent 13q, 17p, and 11q deletions in CLL. CLL Research Consortium institutions provided blood samples from untreated patients (n=206) diagnosed with B-cell CLL between January 2000 and April 2008. All samples were evaluated for the occurrence of cytogenetic abnormalities as well as the expression levels of the miR-15a/miR-16-1 cluster, miR-34b/miR-34c cluster, TP53, and zeta-chain (TCR)–associated protein kinase 70kDa (ZAP70), a surrogate prognostic marker of CLL. The functional relationship between these genes was studied using in vitro gain- and loss-of-function experiments in celllines and primary samples and was validated in a separate cohort of primary CLL samples. Cytogenetic abnormalities; expression levels of the miR-15a/miR-16-1 cluster, miR-34 family, TP53 gene, downstream effectors cyclindependent kinase inhibitor 1A (p21, Cip1) (CDKN1A) and B-cell CLL/lymphoma 2 binding component 3 (BBC3), and ZAP70 gene; genetic interactions detected by chromatin immunoprecipitation. In CLLs with13qdeletions the miR-15a/miR-16-1 cluster directly targetedTP53 (mean luciferase activity for miR-15a vs scrambled control, 0.68 relative light units (RLU) [95%confidence interval {CI}, 0.63–0.73]; P=.02;meanfor miR-16 vs scrambled control, 0.62RLU[95%CI, 0.59–0.65]; P=.02) and its downstream effectors. In leukemic cell lines and primary CLL cells, TP53 stimulated the transcription of miR-15/miR-16-1 as well as miR-34b/miR-34c clusters, and the miR-34b/miR-34c cluster directly targeted theZAP70 kinase(meanluciferase activity for miR-34a vs scrambled control, 0.33RLU [95%CI, 0.30–0.36]; P=.02;meanformiR-34bvsscrambledcontrol,0.31RLU [95%CI, 0.30–0.32];P=.01; and mean for miR-34c vs scrambled control, 0.35 RLU [95% CI, 0.33–0.37]; P=.02). A microRNA/TP53 feedback circuitry is associated with CLL pathogenesis and outcome. This mechanism provides a novel pathogenetic model for the association of 13q deletions with the indolent form of CLL that involves microRNAs, TP53, and ZAP70
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DOI：
10.1073/pnas.0800121105
发表时间：
2008-04-01
影响因子：
11.1
作者：
Calin, George A.;Cimmino, Amelia;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
影响因子：
2.2
作者：
Fabbri, Muller;Croce, Carlo M.;Calin, George A.
通讯作者：
Calin, George A.
影响因子：
20.3
作者：
RAI, KR;SAWITSKY, A;PASTERNACK, BS
通讯作者：
PASTERNACK, BS
影响因子：
158.5
作者：
Rassenti, LZ;Huynh, L;Kipps, TJ
通讯作者：
Kipps, TJ
影响因子：
11.2
作者：
Corney, David C.;Flesken-Nikitin, Andrea;Nikitin, Alexander Yu.
通讯作者：
Nikitin, Alexander Yu.