Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of b-cell chronic lymphocytic leukemia

Muller Fabbri, Arianna Bottoni, Masayoshi Shimizu, Riccardo Spizzo, Milena S. Nicoloso, Simona Rossi, Elisa Barbarotto, Amelia Cimmino, Brett Adair, Sylwia E. Wojcik, Nicola Valeri, Federica Calore, Deepa Sampath, Francesca Fanini, Ivan Vannini, Gerardo Musuraca, Marie Dell'Aquila, Hansjuerg Alder, Ramana V. Davuluri, Laura Z. Rassenti & 9 others Massimo Negrini, Tatsuya Nakamura, Dino Amadori, Neil Elliot Kay, Kanti R. Rai, Michael J. Keating, Thomas J. Kipps, George A. Calin, Carlo M. Croce

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Abstract

Context: 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. Objective: 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. Design, Setting, and Patients: 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 cell lines and primary samples and was validated in a separate cohort of primary CLL samples. Main Outcome Measures: 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. Results: In CLLs with 13q deletions the miR-15a/miR-16-1 cluster directly targeted TP53 (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; mean for miR-16 vs scrambled control, 0.62 RLU [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 the ZAP70 kinase (mean luciferase activity for miR-34a vs scrambled control, 0.33RLU [95% CI, 0.30-0.36];P=.02; mean for miR-34b vs scrambled control, 0.31 RLU [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). Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)59-67
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume305
Issue number1
DOIs
StatePublished - Jan 5 2011

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B-Cell Chronic Lymphocytic Leukemia
MicroRNAs
Chromosome Aberrations
Confidence Intervals
Light
Luciferases
Phosphotransferases
Tumor Suppressor Protein p53
Cell Line
Chromatin Immunoprecipitation
p53 Genes
Protein Kinases
Genes
Biomarkers
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of b-cell chronic lymphocytic leukemia. / 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 Elliot; Rai, Kanti R.; Keating, Michael J.; Kipps, Thomas J.; Calin, George A.; Croce, Carlo M.

In: JAMA - Journal of the American Medical Association, Vol. 305, No. 1, 05.01.2011, p. 59-67.

Research output: Contribution to journalArticle

Fabbri, M, Bottoni, A, Shimizu, M, Spizzo, R, Nicoloso, MS, Rossi, S, Barbarotto, E, Cimmino, A, Adair, B, Wojcik, SE, Valeri, N, Calore, F, Sampath, D, Fanini, F, Vannini, I, Musuraca, G, Dell'Aquila, M, Alder, H, Davuluri, RV, Rassenti, LZ, Negrini, M, Nakamura, T, Amadori, D, Kay, NE, Rai, KR, Keating, MJ, Kipps, TJ, Calin, GA & Croce, CM 2011, 'Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of b-cell chronic lymphocytic leukemia', JAMA - Journal of the American Medical Association, vol. 305, no. 1, pp. 59-67. https://doi.org/10.1001/jama.2010.1919
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 Elliot ; Rai, Kanti R. ; Keating, Michael J. ; Kipps, Thomas J. ; Calin, George A. ; Croce, Carlo M. / Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of b-cell chronic lymphocytic leukemia. In: JAMA - Journal of the American Medical Association. 2011 ; Vol. 305, No. 1. pp. 59-67.
@article{3935d9b7b2774251be92e5890b00254c,
title = "Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of b-cell chronic lymphocytic leukemia",
abstract = "Context: 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. Objective: 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. Design, Setting, and Patients: 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 cell lines and primary samples and was validated in a separate cohort of primary CLL samples. Main Outcome Measures: 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. Results: In CLLs with 13q deletions the miR-15a/miR-16-1 cluster directly targeted TP53 (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; mean for miR-16 vs scrambled control, 0.62 RLU [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 the ZAP70 kinase (mean luciferase activity for miR-34a vs scrambled control, 0.33RLU [95{\%} CI, 0.30-0.36];P=.02; mean for miR-34b vs scrambled control, 0.31 RLU [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). Conclusions: 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.",
author = "Muller Fabbri and Arianna Bottoni and Masayoshi Shimizu and Riccardo Spizzo and Nicoloso, {Milena S.} and Simona Rossi and Elisa Barbarotto and Amelia Cimmino and Brett Adair and Wojcik, {Sylwia E.} and Nicola Valeri and Federica Calore and Deepa Sampath and Francesca Fanini and Ivan Vannini and Gerardo Musuraca and Marie Dell'Aquila and Hansjuerg Alder and Davuluri, {Ramana V.} and Rassenti, {Laura Z.} and Massimo Negrini and Tatsuya Nakamura and Dino Amadori and Kay, {Neil Elliot} and Rai, {Kanti R.} and Keating, {Michael J.} and Kipps, {Thomas J.} and Calin, {George A.} and Croce, {Carlo M.}",
year = "2011",
month = "1",
day = "5",
doi = "10.1001/jama.2010.1919",
language = "English (US)",
volume = "305",
pages = "59--67",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
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TY - JOUR

T1 - Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of b-cell chronic lymphocytic leukemia

AU - Fabbri, Muller

AU - Bottoni, Arianna

AU - Shimizu, Masayoshi

AU - Spizzo, Riccardo

AU - Nicoloso, Milena S.

AU - Rossi, Simona

AU - Barbarotto, Elisa

AU - Cimmino, Amelia

AU - Adair, Brett

AU - Wojcik, Sylwia E.

AU - Valeri, Nicola

AU - Calore, Federica

AU - Sampath, Deepa

AU - Fanini, Francesca

AU - Vannini, Ivan

AU - Musuraca, Gerardo

AU - Dell'Aquila, Marie

AU - Alder, Hansjuerg

AU - Davuluri, Ramana V.

AU - Rassenti, Laura Z.

AU - Negrini, Massimo

AU - Nakamura, Tatsuya

AU - Amadori, Dino

AU - Kay, Neil Elliot

AU - Rai, Kanti R.

AU - Keating, Michael J.

AU - Kipps, Thomas J.

AU - Calin, George A.

AU - Croce, Carlo M.

PY - 2011/1/5

Y1 - 2011/1/5

N2 - Context: 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. Objective: 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. Design, Setting, and Patients: 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 cell lines and primary samples and was validated in a separate cohort of primary CLL samples. Main Outcome Measures: 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. Results: In CLLs with 13q deletions the miR-15a/miR-16-1 cluster directly targeted TP53 (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; mean for miR-16 vs scrambled control, 0.62 RLU [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 the ZAP70 kinase (mean luciferase activity for miR-34a vs scrambled control, 0.33RLU [95% CI, 0.30-0.36];P=.02; mean for miR-34b vs scrambled control, 0.31 RLU [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). Conclusions: 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.

AB - Context: 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. Objective: 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. Design, Setting, and Patients: 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 cell lines and primary samples and was validated in a separate cohort of primary CLL samples. Main Outcome Measures: 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. Results: In CLLs with 13q deletions the miR-15a/miR-16-1 cluster directly targeted TP53 (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; mean for miR-16 vs scrambled control, 0.62 RLU [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 the ZAP70 kinase (mean luciferase activity for miR-34a vs scrambled control, 0.33RLU [95% CI, 0.30-0.36];P=.02; mean for miR-34b vs scrambled control, 0.31 RLU [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). Conclusions: 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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