A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma

Elena Beltran, Vicente Fresquet, Javier Martinez-Useros, Jose A. Richter-Larrea, Ainara Sagardoy, Izaskun Sesma, Luciana L. Almada, Santiago Montes-Moreno, Reiner Siebert, Stefan Gesk, Maria J. Calasanz, Raquel Malumbres, Melissa Rieger, Felipe Prosper, Izidore Lossos, Miguel Angel Piris, Martin E. Fernandez-Zapico, Jose A. Martinez-Climent

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G 1-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.

Original languageEnglish
Pages (from-to)12461-12466
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number30
DOIs
StatePublished - Jul 26 2011

Fingerprint

Mantle-Cell Lymphoma
Cyclin D1
Lymphoma
Therapeutics
Apoptosis
Genetic Translocation

Keywords

  • ABT-737
  • Cyclin-D1 inhibitor drugs
  • Mouse model of MCL
  • Oncogene addiction
  • Targeted therapy

ASJC Scopus subject areas

  • General

Cite this

A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma. / Beltran, Elena; Fresquet, Vicente; Martinez-Useros, Javier; Richter-Larrea, Jose A.; Sagardoy, Ainara; Sesma, Izaskun; Almada, Luciana L.; Montes-Moreno, Santiago; Siebert, Reiner; Gesk, Stefan; Calasanz, Maria J.; Malumbres, Raquel; Rieger, Melissa; Prosper, Felipe; Lossos, Izidore; Piris, Miguel Angel; Fernandez-Zapico, Martin E.; Martinez-Climent, Jose A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 30, 26.07.2011, p. 12461-12466.

Research output: Contribution to journalArticle

Beltran, E, Fresquet, V, Martinez-Useros, J, Richter-Larrea, JA, Sagardoy, A, Sesma, I, Almada, LL, Montes-Moreno, S, Siebert, R, Gesk, S, Calasanz, MJ, Malumbres, R, Rieger, M, Prosper, F, Lossos, I, Piris, MA, Fernandez-Zapico, ME & Martinez-Climent, JA 2011, 'A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 30, pp. 12461-12466. https://doi.org/10.1073/pnas.1018941108
Beltran, Elena ; Fresquet, Vicente ; Martinez-Useros, Javier ; Richter-Larrea, Jose A. ; Sagardoy, Ainara ; Sesma, Izaskun ; Almada, Luciana L. ; Montes-Moreno, Santiago ; Siebert, Reiner ; Gesk, Stefan ; Calasanz, Maria J. ; Malumbres, Raquel ; Rieger, Melissa ; Prosper, Felipe ; Lossos, Izidore ; Piris, Miguel Angel ; Fernandez-Zapico, Martin E. ; Martinez-Climent, Jose A. / A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 30. pp. 12461-12466.
@article{fc325bcbb30c4692bdb7739fb22cc0e5,
title = "A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma",
abstract = "The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G 1-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.",
keywords = "ABT-737, Cyclin-D1 inhibitor drugs, Mouse model of MCL, Oncogene addiction, Targeted therapy",
author = "Elena Beltran and Vicente Fresquet and Javier Martinez-Useros and Richter-Larrea, {Jose A.} and Ainara Sagardoy and Izaskun Sesma and Almada, {Luciana L.} and Santiago Montes-Moreno and Reiner Siebert and Stefan Gesk and Calasanz, {Maria J.} and Raquel Malumbres and Melissa Rieger and Felipe Prosper and Izidore Lossos and Piris, {Miguel Angel} and Fernandez-Zapico, {Martin E.} and Martinez-Climent, {Jose A.}",
year = "2011",
month = "7",
day = "26",
doi = "10.1073/pnas.1018941108",
language = "English",
volume = "108",
pages = "12461--12466",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "30",

}

TY - JOUR

T1 - A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma

AU - Beltran, Elena

AU - Fresquet, Vicente

AU - Martinez-Useros, Javier

AU - Richter-Larrea, Jose A.

AU - Sagardoy, Ainara

AU - Sesma, Izaskun

AU - Almada, Luciana L.

AU - Montes-Moreno, Santiago

AU - Siebert, Reiner

AU - Gesk, Stefan

AU - Calasanz, Maria J.

AU - Malumbres, Raquel

AU - Rieger, Melissa

AU - Prosper, Felipe

AU - Lossos, Izidore

AU - Piris, Miguel Angel

AU - Fernandez-Zapico, Martin E.

AU - Martinez-Climent, Jose A.

PY - 2011/7/26

Y1 - 2011/7/26

N2 - The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G 1-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.

AB - The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G 1-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors.

KW - ABT-737

KW - Cyclin-D1 inhibitor drugs

KW - Mouse model of MCL

KW - Oncogene addiction

KW - Targeted therapy

UR - http://www.scopus.com/inward/record.url?scp=79961079532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79961079532&partnerID=8YFLogxK

U2 - 10.1073/pnas.1018941108

DO - 10.1073/pnas.1018941108

M3 - Article

C2 - 21746927

AN - SCOPUS:79961079532

VL - 108

SP - 12461

EP - 12466

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 30

ER -