antonio ruz-vela´s research goals

Carlos Martínez-Alonso

•Immnunology & Oncology•Nature. 1989 Nov 2;342(6245):82-5.•Nature. 1990 Jul 19;346(6281):271-4.•Nature. 1993 Jan 21;361(6409):213.•Nature. 1999 Aug 19;400(6746):723-4.

RESEARCH GOALS

1) Decoding/Dissecting the sub-cellular and molecular regulation of the oncogene BCL-2 in B-cell lymphomas2) Identification of novel oncogenes in a novel murine B-cell leukaemia model

Pro-B cell

Genetic model of disease: BCL2 translocation in Follicular LymphomaGenetic model of disease: BCL2 translocation in Follicular Lymphoma

Pre-BII Early Pre-BI Pre-BI ImmatureB cell

TransitionalB cell

MatureB cell

HSC

B220+IgM-CD23-ckit+CD43+CD24+CD23-

V-DJ/IgHl5Pre-BCRCD19+

V-J/IgLBCR (IgM+)

Auto-Ag

IgD+IgM+CD24+CD23-CD21-

IgD++IgM+CD24-CD23+CD21+

Sca-1+Lin-ckit+

CD25+D-J/IgH

IL7R/IL7

Tsujimoto Y, et.al .Science. 1984 Nov 30;226(4678):1097-9.

BCL2 ∅

System biology approach: BCL2 interactomeSystem biology approach: BCL2 interactome

Oncogenes

•HRAS•RAF1

•MYC (T. F)•BCL6 (T. F)•NFKB1 (T. F)

Tumour Suppressors

•APAF1• CASP3•BAD•BAX•TP53 (T. F)

Functional biased screen in B-cell lymphomas(BCL2 gain-of-function approach)

Ruiz-Vela A, et. al. EMBO J. 1999 Sep 15;18(18):4988-98.

Bcl-2BH4 BH3BH1BH2TM

Ruiz-Vela A, et. al. FEBS Lett. 2001 Jul 13;501(1):79-83.

Synthetic Biology

Functional biased screen (BCL2 gain-of-function approach)Functional biased screen (BCL2 gain-of-function approach)

Brás A, Ruiz-Vela A, et. al. FASEB J. 1999 May;13(8):931-44.Ruiz-Vela A, et. al. EMBO J. 1999 Sep 15;18(18):4988-98.Ruiz-Vela A, et.al. J Exp Med. 2001 Aug 6;194(3):247-54.

BCL-2 as a therapeutic targetBCL-2 as a therapeutic target

Synthetic Biology

CD19+IgM+

B220+IgM-CD43+

Early Pre-BI/GFP

IL7R/IL7

Ruiz-Vela A, et.al. J Exp Med. 2001 Aug 6;194(3):247-54.

Genetic model of disease: B-cell Chronic Lymphocytic Leukemia (B-CLL)Genetic model of disease: B-cell Chronic Lymphocytic Leukemia (B-CLL)

Ruiz-Vela A, et.al. Oncogene. 2005 Jul 28;24(32):5119-24.

Synthetic Biology

Ruiz-Vela A, et.al. Oncogene. 2005 Jul 28;24(32):5119-24.

B-CCL Non-biased screen (Genome-wide DNA microarrays)B-CCL Non-biased screen (Genome-wide DNA microarrays)

Ruiz-Vela A, et.al. Oncogene. 2005 Jul 28;24(32):5119-24.

Functional biased screen (ZAP70 gain-of-function approach)Functional biased screen (ZAP70 gain-of-function approach)

Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1.Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ.Nature. 2003 Dec 11;426(6967):671-6

BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis.Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB, Gygi SP, Korsmeyer SJ.Nature. 2003 Aug 21;424(6951):952-6.

Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis.Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA, Korsmeyer SJ.Nature. 1999 Aug 26;400(6747):886-91.

HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint.Kawabe T, Muslin AJ, Korsmeyer SJ.Nature. 1997 Jan 30;385(6615):454-8.

Altered Hox expression and segmental identity in Mll-mutant mice.Yu BD, Hess JL, Horning SE, Brown GA, Korsmeyer SJ.Nature. 1995 Nov 30;378(6556):505-8.PMID: 7477409

BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax.Yin XM, Oltvai ZN, Korsmeyer SJ.Nature. 1994 May 26;369(6478):321-3.PMID: 8183370

Hox11 controls the genesis of the spleen.Roberts CW, Shutter JR, Korsmeyer SJ.Nature. 1994 Apr 21;368(6473):747-9.PMID: 7908720

Bcl-2 maintains B cell memory.Nuñez G, Hockenbery D, McDonnell TJ, Sorensen CM, Korsmeyer SJ.Nature. 1991 Sep 5;353(6339):71-3.PMID: 1908951

Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18).McDonnell TJ, Korsmeyer SJ.Nature. 1991 Jan 17;349(6306):254-6.

Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death.Hockenbery D, Nuñez G, Milliman C, Schreiber RD, Korsmeyer SJ.Nature. 1990 Nov 22;348(6299):334-6.

A uniform deleting element mediates the loss of kappa genes in human B cells.Siminovitch KA, Bakhshi A, Goldman P, Korsmeyer SJ.Nature. 1985 Jul 18-24;316(6025):260-2.

Stan J. Korsmeyer

•Hematology and Oncology

RESEARCH GOALS

1) Decoding/Dissecting the molecular regulation of the tumour suppresssor BAX & BAK in MEFs

Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha.Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, Korsmeyer SJ.Science. 2006 Apr 28;312(5773):572-6.

Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells.Opferman JT, Iwasaki H, Ong CC, Suh H, Mizuno S, Akashi K, Korsmeyer SJ.Science. 2005 Feb 18;307(5712):1101-4.

BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis.Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ.Science. 2003 Apr 4;300(5616):135-9.

Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ.Science. 2001 Apr 27;292(5517):727-30.

Lindsten., Mol Cell. 2000 Dec;6(6):1389-99.

BAX-/-, BAK-/-

BAX-/-, BAK+/-

BAX+/-, BAK-/-

BAX+/-, BAK+/-

Genetic model of disease: BAX & BAK doubly KO (DKO) in lymphomagenesisGenetic model of disease: BAX & BAK doubly KO (DKO) in lymphomagenesis

CED9Bcl-2Bcl-xLMcl-1A1/Bfl-1Boo/DivaNr13

BH4 BH3 BH1 BH2 TM

TMBaxBakBok/Mtd

BidBadBik/NbkBlkHrkBim/BodNixNoxa

BH3 BH1 BH2

Synthetic Biology

BAX & BAK -dependent Remodeling of the MitochondrialBAX & BAK -dependent Remodeling of the MitochondrialCristae and Cyt-c ReleaseCristae and Cyt-c Release

Scorrano L., Dev Cell. 2002 Jun;2(1):55-67.

IMboundary

Outermembrane Cristae

Class I

Class II

Class III

Acehan D., Mol Cell. 2002 Feb;9(2):423-32.

Liu et al., Cell. 1996 Jul 12;86(1):147-57.

System biology approach: BAX & BAK interactomeSystem biology approach: BAX & BAK interactome

Oncogenes

•MYC•BCL2•RELA

Tumour Suppressors

•CASP9• CASP3•CASP7•BID•TP53

CASP-3, -7

IRE-1IRE-1

TRAF2

CASP-12CASP-12

CASP-3, -7

RAIDD

CASP-2CASP-2

Functional biased screen in MEFs (BAX & BAK loss-of-function approach)Functional biased screen in MEFs (BAX & BAK loss-of-function approach)

Miguel Angel Piris Pinilla

•Oncogenomic Pathology

RESEARCH GOALS

1) Decoding/Dissecting the genetic regulation of the oncogene MCL-1 in B-cell lymphomas

Leukemia. 2007 Sep;21(9):1984-91. Epub 2007 Jul 5.

Genetic model of disease: MCL1 overexpression in human B-CLLGenetic model of disease: MCL1 overexpression in human B-CLL

MCL1 Gain-of-FunctionMCL1 Gain-of-Function

Ruiz-Vela A, et.al. Blood. 2008 Feb 1;111(3):1665-76.

Synthetic Biology

Wide Genome Gene Expression of MCL1-OverexpressingWide Genome Gene Expression of MCL1-OverexpressingB-Cell Lymphomas:B-Cell Lymphomas: (Agilent, PantherDB and GEPAS Tools) (Agilent, PantherDB and GEPAS Tools)

Network modeling.Network modeling.

Ruiz-Vela A et al. Blood 2008;111:1665-1676

©2008 by American Society of Hematology

Gene-network cross-validation in human primary follicular B-cell lymphomas.

Ruiz-Vela A et al. Blood 2008;111:1665-1676

©2008 by American Society of Hematology

RESEARCH GOALS

1) Decoding/Dissecting the oncogenic potential and properties of human embryonic stem cells

In Vitro Cell Dev Biol Anim. 2010 Apr;46(3-4):317-26.

Celular model of therapy: Human Embryonic Stem CellsCelular model of therapy: Human Embryonic Stem Cells

Aging (Albany NY). 2011 May;3(5):494-508. Nat Genet. 2008 May;40(5):499-507.

Synthetic Biology

Oct4/Nanog overexpression promotes in vivo tumorigenic and Oct4/Nanog overexpression promotes in vivo tumorigenic and metastatic abilities of A549-Oct4/Nanog cells.metastatic abilities of A549-Oct4/Nanog cells.

Chiou S et al. Cancer Res 2010;70:10433-10444

©2010 by American Association for Cancer Research

Synthetic Biology

Cellular biology approach: hESCs microenvironmentIn vivo embryonic microenvironmentIn vivo embryonic microenvironment

PLoS One. 2008 Jan 2;3(1):e1384.

In vitro embryonic microenvironment

System biology approach: ALB interactomeSystem biology approach: ALB interactome

Ruiz-Vela A, et.al. Stem Cell Rev. 2011 Nov;7(4):898-909.

ßiochemical model of therapy: Adipogenic Transdifferentiation in ßiochemical model of therapy: Adipogenic Transdifferentiation in CarcinomasCarcinomas

Cellular biology approach: Mesenchymal Stem Cell Differentiation

Ruiz-Vela A, et.al. Stem Cell Rev. 2011 Nov;7(4):898-909.

Adipogenic Transdifferentiation biased screen (15 Adipogenic Transdifferentiation biased screen (15 regulators)regulators)

Future approachesFuture approaches::

Oncology: To study MCL1, KLF2/4, Sox2, Oct3/4 and Wnt signaling in B-CLL, MM, and Germ tumours. Epigenetics:To study MCL1-induced cell fate reprogramming at the level of histone modifications and their relation with Wnt signaling

Mouse Genetics: Generation & Characterization of MCL1 , KLF2/4, Sox2, and Oct3/4 transgenic mice using stem-cell specific and tissue-

specific promoters.

iPS Biology (KLF2/4, Sox2, Myc, Oct3/4):To study the iPS potential of MCL1-dependent targets: CBX7, NOTCH2, HOXA4, KLF2 (Ruiz-Vela et al., Blood 2008,

11(3), 1665-76)