Oncotarget

Methodological Reports:

Mantle cell lymphoma-like lymphomas in c-myc-3’RR/p53+/- mice and c-myc-3’RR/Cdk4R24C mice: differential oncogenic mechanisms but similar cellular origin

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Oncotarget. 2012; 3:586-593. https://doi.org/10.18632/oncotarget.474

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Pauline Rouaud, Rémi Fiancette, Christelle Vincent-Fabert, Virginie Magnone, Michel Cogné, Pierre Dubus and Yves Denizot _

Abstract

Pauline Rouaud1, Rémi Fiancette1, Christelle Vincent-Fabert1, Virginie Magnone2, Michel Cogné1, Pierre Dubus3 and Yves Denizot1

1 UMR CNRS 7276, Faculté de Médecine, Limoges, France

2 CNRS and University of Nice Sophia Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097, Sophia Antipolis, France

3 EA2406, Université de Bordeaux, Bordeaux, France

Received: April 3, 2012; Accepted: April 28, 2012; Published: May 9, 2012;

Keywords: Mantle cell lymphoma, c-myc

Correspondence:

Yves Denizot, email:

Abstract

Mantle cell lymphoma (MCL) is a malignant lymphoproliferative B-cell disorder that does not occur spontaneously in mice but experimental mice model have been developed. Recently two different mice models prone to develop MCL-like lymphomas were generated: c-myc-3’RR/Cdk4R24C mice and c-myc-3’RR/p53+/- mice. Comparison of their gene expression profiles does not highlight specific differences other than those in relation with their specific mutational status (i.e., Cdk4R24C mutation or p53 mutation). We propose that similarly to typical human MCL and its blastoid or cyclin-D1 variants that correspond to the same genetic entity, MCL-like lymphomas of c-myc-3’RR/p53+/- mice and c-myc-3’RR/Cdk4R24C mice represent a spectrum of the same entity.


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INTRODUCTION

Mantle cell lymphoma (MCL) is a malignant lymphoproliferative B-cell disorder derived from naïve pregerminal center CD5+ cells [1]. MCL is strongly associated with the t(11,14) chromosomal translocation leading to overexpression of cyclin D1. Cyclin D1-negative MCL do no express high amounts of cyclin D1 but elevated cyclin D2 or cyclin D3 ones and share the same secondary genetic aberrations that typical MCL supporting the concept that they correspond to the same genetic entity [1]. MCL does not occur spontaneously in mice but experimental mice model have been developed. Old Eµ-cyclin D1 transgenic mice developed CD19+IgM+CD5+CD23- MCL under stimulation by pristine, a pro-inflammatory tumor promoter [2]. Interleukin 14 alpha (IL-14α)/c-myc double transgenic mice developed lymphomas reproducing many features of blastoid variant of MCL [3]. Recently we generated two different mice models prone to develop MCL-like lymphomas. The first one uses the Cdk4-Arg24Cys (R24C) mutation that abolishes the ability of all four INK4 members to bind Cdk4. Disruption of Cdk4 regulation by INK4 while c-myc is overexpressed in B-cells (in a c-myc-3’RR transgenic background prone to develop Burkitt lymphoma (BL)-like lymphomas [4]) leads to the development (in double mutant c-myc-3’RR/Cdk4R24C mice) of lymphoid malignancies closely resembling human MCL [5]. The second is relevant to the frequent loss of p53 function observed in human lymphomas, underscoring its critical role in suppressing the emergence of incipient tumors. Double mutant c-myc-3’RR/p53+/- mice developed a wide pattern of lymphomas including MCL-like lymphomas [6]. It remains unclear what are the common molecular and genetic pathways explaining the convergence of these two mice models towards the same lymphoma phenotype. In both situations, MCL-like lymphomas express similar membrane B-cell differentiation markers (B220+CD19+IgM+IgD+ CD5+CD23-) but arise with different kinetics (3 months vs 6 months for c-myc-3’RR/p53+/- mice and c-myc-3’RR/Cdk4R24C mice, respectively), with a different proteomic signature (Cdk6/cyclin D complexes vs Cdk4/cyclin D complexes for c-myc-3’RR/p53+/- mice and c-myc-3’RR/Cdk4R24C mice, respectively), and in relation with a different mutational status (p53 deficiency vs disruption of Cdk4 regulation by INK4). Gene arrays have proven effective in establishing molecularly defined subgroups within defined tumor entities. We explored the potential similar biological entity of these two mice models of MCL-like lymphomas by comparing their gene expression profiles.

Table 1: Genes implicated in growth, metabolism and signalling processes.

Log2
ratio

 p-value

log score

Name

Systematic
Name

Description

A-B

A-B

A-B

Tppp

NM_182839

polymerization promoting protein

-5.97

0.03

4.48

Prkcc

NM_011102

protein kinase C, gamma

-4.35

0.03

4.28

Gchfr

NM_177157

GTP cyclohydrolase I feedback regulator

-3.91

0.03

4.14

Chit1

NM_027979

chitinase 1 (chitotriosidase)

-5.14

0.03

4.11

Ahnak

NM_001039959

nucleoprotein (desmoyokin), TV 3

-4.48

0.03

3.95

Trf

NM_133977

transferrin

-4.41

0.03

3.94

Apoc1

NM_007469

apolipoprotein C-I, TV 1

-3.74

0.03

3.94

Macrod2

NM_028387

MACRO domain containing 2, TV 2

2.89

0.03

3.56

Rfx2

NM_009056

regulatory factor X, TV 2

-3.31

0.03

3.52

Ctse

NM_007799

cathepsin E

-4.17

0.03

3.46

Cdkn2a

NM_009877

cyclin-dependent kinase inhibitor 2A, TV 1

4.17

0.03

3.45

Slc40a1

NM_016917

solute carrier family 40, M 1

-5.21

0.03

3.43

Igf1

NM_010512

insulin-like growth factor 1, TV 1

-3.1

0.03

3.43

Igf2bp3

NM_023670

insulin-like growth factor 2 mRNA binding protein 3

2.85

0.03

3.38

Slc2a6

NM_172659

solute carrier family 2, M 6

2.51

0.03

3.31

Ngfr

NM_033217

nerve growth factor receptor

-3.13

0.03

3.28

Camk4

NM_009793

calcium/calmodulin-dependent protein kinase IV

3.42

0.03

3.25

Rtn4rl1

NM_177708

reticulon 4 receptor-like 1

-4.58

0.03

3.19

Ear11

NM_053113

eosinophil-associated, ribonuclease A family, M 11

-2.64

0.03

3.14

Ccnb1

NM_172301

cyclin B1

2.9

0.03

3.11

Rasal1

NM_013832

RAS protein activator like 1 (GAP1 like)

2.67

0.03

3.10

As3mt

NM_020577

arsenic (+3 oxidation state) methyltransferase

-2.71

0.03

3.08

Ppl

NM_008909

periplakin

-2.79

0.03

3.06

Spic

NM_011461

spi-C transcription factor

-3.85

0.03

2.97

Eif2c2

NM_153178

eukaryotic translation initiation factor 2C

3.42

0.03

2.95

Ak4

NM_001177602

adenylate kinase 4, TV 1

3.54

0.03

2.93

Timeless

NM_001164081

timeless homolog (Drosophila),TV 4

2.57

0.03

2.89

Rgs12

NM_173402

regulator of G-protein signaling 12, TV 1

3.1

0.03

2.86

Ccr3

NM_009914

chemokine (C-C motif) receptor 3

-2.74

0.03

2.79

Mrap

NM_029844

melanocortin 2 receptor accessory protein

-2.36

0.03

2.79

Cdc20

NM_023223

cell division cycle 20 homolog

2.26

0.03

2.77

Adarb1

NM_001024837

adenosine deaminase B1, TV 2

2.25

0.03

2.75

Cotl1

NM_028071

coactosin-like 1 (Dictyostelium)

-2.13

0.03

2.69

Trip13

NM_027182

thyroid hormone receptor interactor 13

2.3

0.03

2.65

Atp6v1c2

NM_133699

ATPase, lysosomal V1 subunit C2, TV 2

-2.83

0.03

2.58

Slc43a3

NM_021398

solute carrier family 43, M 3

3.27

0.03

2.46

Sbk1

NM_145587

SH3-binding kinase 1

-2.45

0.03

2.38

Vcam1

NM_011693

vascular cell adhesion molecule 1

-4.91

0.03

2.37

Kcnj16

NM_010604

potassium inwardly-rectifying channel, subfamily J, M 16

-2

0.03

2.33

Lmo1

NM_057173

LIM domain only 1

2.01

0.03

2.30

Osbpl5

NM_024289

oxysterol binding protein-like 5, TV 1

-2.17

0.03

2.30

Tmco6

NM_028036

transmembrane and coiled-coil domains 6

-2.01

0.03

2.30

Serpinb3c

NM_201363

serine (or cysteine) peptidase inhibitor, clade B, M 3C

2.63

0.03

2.25

Trim11

NM_053168

tripartite motif-containing 11

-2.06

0.03

2.24

Slc16a9

NM_025807

solute carrier family 16 , M 9

-2.07

0.03

2.23

Fxyd6

NM_022004

FXYD domain-containing ion transport regulator 6

2.13

0.03

2.22

Gstm5

NM_010360

glutathione S-transferase, mu 5

2.52

0.03

2.19

Slc34a1

NM_011392

solute carrier family 34 (sodium phosphate), M 1

-2.82

0.03

2.14

Rnf157

ENSMUST00000149682

ring finger protein 157

2.52

0.03

2.124

Nek2

NM_010892

NIMA (never in mitosis gene a)-related expressed kinase 2

2.57

0.03

2.11

C6

NM_016704

complement component 6

-2.18

0.03

2.05

H60a

NM_010400

histocompatibility 60a

-6.18

0.03

2.04

septin3

NM_011889

septin 3

-6.18

0.03

2.04

Ear10

NM_053112

eosinophil-associated, ribonuclease A family, M 10

-2.2

0.03

1.99

Kctd17

NM_001081367

potassium channel tetramerisation domain containing 17

3.64

0.03

1.91

Casc4

NM_001205369

cancer susceptibility candidate 4, TV 3

2.44

0.03

1.89

Tcp11l2

NM_146008

t-complex 11 like 2

-2.88

0.03

1.83

Mybl2

NM_008652

myeloblastosis oncogene-like 2

2.16

0.03

1.83

Prkar2a

NM_008924

protein kinase, cAMP dependent regulatory, type II alpha

2.1

0.03

1.81

Tcp11

NM_013687

t-complex protein 11, TV 1

-2.04

0.03

1.81

Trerf1

NM_172622

transcriptional regulating factor 1,TV 2

3.07

0.03

1.80

Pvrl2

NM_008990

poliovirus receptor-related 2, TV 1

-4.17

0.03

1.78

Prkar2b

NM_011158

protein kinase, cAMP dependent regulatory, type II beta

-3.46

0.03

1.78

Melk

NM_010790

maternal embryonic leucine zipper kinase

2.23

0.03

1.75

Cdca3

NM_013538

cell division cycle associated 3

2.21

0.03

1.74

B3gnt8

NM_146184

betaGal beta-1,3-N-acetylglucosaminyltransferase 8, TV 1

-2.19

0.03

1.71

Nradd

NM_026012

neurotrophin receptor associated death domain

2.29

0.03

1.68

S100a5

NM_011312

S100 calcium binding protein A5

-2.38

0.03

1.68

Antxr1

NM_054041

anthrax toxin receptor 1

2.25

0.04

1.64

Pear1

NM_028460

platelet endothelial aggregation receptor 1, TV 1

-2.6

0.04

1.62

Akap13

ENSMUST00000136989

A kinase (PRKA) anchor protein 13

-2.23

0.04

1.62

Ebf3

NM_010096

early B-cell factor 3, TV 3

2.86

0.04

1.60

Tk1

NM_009387

thymidine kinase 1

2.46

0.04

1.57

Rgs11

NM_001081069

regulator of G-protein signaling 11

-2.22

0.04

1.57

Gm4910

XM_141816

predicted pseudogene 4910

-2.22

0.04

1.56

Ell3

NM_145973

elongation factor RNA polymerase II-like 3

-3.12

0.04

1.55

Etl4

NM_001081006

enhancer trap locus 4, transcript variant c

3.4

0.04

1.50

Syce2

NM_027954

synaptonemal complex central element protein 2, TV 2

3.17

0.04

1.47

LOC100042049

NR_004442

ribosomal protein L22 like 1 pseudogene

-2.17

0.04

1.38

Sorcs2

NM_030889

sortilin-related VPS10 domain containing receptor 2

-2.12

0.04

1.38

Crip2

NM_024223

cysteine rich protein 2

-4.51

0.04

1.37

Wnk2

NM_029361

WNK lysine deficient protein kinase 2

3.76

0.04

1.36

Samd9l

NM_010156

sterile alpha motif domain containing 9-like

-2.09

0.04

1.36

Hoxb6

NM_008269

homeobox B6

-2.23

0.04

1.35

Rpl22l1

NM_026517

ribosomal protein L22 like 1

-2.02

0.04

1.34

Crip1

NM_007763

cysteine-rich protein 1

-4.05

0.04

1.31

Enkur

NM_027728

enkurin

-3.01

0.04

1.30

Ear2

NM_007895

eosinophil-associated, ribonuclease A family,M 2

-3.45

0.04

1.29

Cdca5

NM_026410

cell division cycle associated 5

2.04

0.04

1.23

Mrc1

NM_008625

 mannose receptor, C type 1

-2.61

0.04

1.22

Ear12

NM_001012766

eosinophil-associated, ribonuclease A family, M 12

-2.29

0.04

1.20

Ehf

NM_007914

ets homologous factor

2.89

0.04

1.16

Ssbp2

NM_024272

single-stranded DNA binding protein 2, TV 2

2.49

0.04

1.14

Phlda3

NM_013750

pleckstrin homology-like domain, family A, M 3

-4.08

0.04

1.14

Whsc1

NM_001177884

Wolf-Hirschhorn syndrome candidate 1, TV 3

2.16

0.04

1.11

Gm2a

NM_010299

GM2 ganglioside activator protein

-2.21

0.04

1.11

Armc2

NM_001034858

armadillo repeat containing 2

3.03

0.04

1.09

Comparison of transcriptoma of c-myc-3’RR/Cdk4R24C and c-myc-3’RR/p53+/- MCL-like lymphomas. Among these 44,000 genes, 176 significantly differed. A Log score >2, a Log ratio >2 or <-2 and a p<0.05 was used as cut of. A: c-myc-3’RR/p53+/- MCL-like lymphomas; B: c-myc-3’RR/Cdk4R24C MCL-like lymphomas; M: member; TV: transcript variant.

Material and Methods

 

Our research has been approved by the ethics committee review board of our University (Limoges, France) and hospital (CHU Dupuytren, Limoges, France). Animal works has been conducted according to French laws. c-myc-3’RR transgenic mice are prone to BL-like lymphomas [4]. In c-myc-3’RR mice, c-myc is specifically expressed from the pre-B to the mature B-cell stages; the 3’RR being active in late B cell lymphopoiesis [7-9]. Generation of c-myc-3’RR/Cdk4R24C and c-myc-3’RR/p53+/- mice in similar genetic background and their MCL-like lymphoma development have been previously reported [5, 6]. mRNA was extracted from MCL-like lymphoma cases by sorting tumoral cells with CD19-coupled beads (Miltenyi Biotech, Bergisch Gladbach, Germany). Microarray experiments were done in “Nice - Sophia Antipolis Microarray Facility” (France). Statistical analysis was made with the Bioconductor open source software, particularly its Limma package. The microarray data presented in this article have been submitted to the Gene Expression Omnibus database (www.ncbi.nlm.nih.gov/geo/) under the accession numbers GSE36808.

Results and Discussion

The gene expression profile of MCL-like lymphomas of c-myc-3’RR/Cdk4R24C mice was compared with the one of c-myc-3’RR/p53+/- mice using an array of 44,000 genes. A Log score >2, a Log ratio >2 or <-2 and a p<0.05 was used as cut of. Among these 44,000 genes, only 176 significantly differed (Tables 1, 2, 3 and 4). Noticeably, differential expression of multiple genes involved in growth, metabolism and signalling (97/176, 55.1%, Table 1), diabetes and obesity (31/176, 17.6%, Table 2)and cellular architecture (23/176, 13.0%, Table 3) were found. Thirty two unknown genes significantly differed (32/176, 18.1%, Table 4). Of note some genes can be found both in Table 1, 2 and/or 3.

Table 2: Genes implicated in diabetes and obesity.

Log2
ratio

 p-value

log score

Name

Systematic
Name

Description

A-B

A-B

A-B

Abcc8

NM_011510

ATP-binding cassette, sub-family C,  M 8

4.11

0.03

4.02

Ahnak

NM_001039959

nucleoprotein (desmoyokin), TV 3

-4.48

0.03

3.95

Trf

NM_133977

transferrin

-4.41

0.03

3.94

Apoc1

NM_007469

apolipoprotein C-I, TV 1

-3.74

0.03

3.94

Cr2

NM_007758

complement receptor 2

-3.62

0.03

3.77

Cdkn2a

NM_009877

cyclin-dependent kinase inhibitor 2A, TV 1

4.17

0.03

3.45

Gfra2

NM_008115

glial derived neurotrophic factor family receptor alpha 2

-4.48

0.03

3.44

Igf1

NM_010512

insulin-like growth factor 1, TV 1

-3.1

0.03

3.43

Igf2bp3

NM_023670

insulin-like growth factor 2 mRNA binding protein 3

2.85

0.03

3.38

Hmox1

NM_010442

heme oxygenase (decycling) 1

-3.87

0.03

3.29

Gstt1

NM_008185

glutathione S-transferase, theta 1

2.7

0.03

3.17

Rcan2

NM_207649

regulator of calcineurin 2, TV 1

3.87

0.03

3.16

Tub

NM_021885

tubby candidate gene

-3.29

0.03

3.13

Osbpl3

NM_001163645

oxysterol binding protein-like 3, TV 2

2.49

0.03

2.99

Mgll

NM_001166251

monoglyceride lipase, TV 1

2.1

0.03

2.85

Srd5a1

NM_175283

steroid 5 alpha-reductase 1

3.31

0.03

2.42

Rgs16

NM_011267

regulator of G-protein signaling 16

2.96

0.03

2.23

Cbs

NM_144855

cystathionine beta-synthase, TV 1

3.82

0.03

2.19

Alox5

NM_009662

arachidonate 5-lipoxygenase

2.18

0.03

2.19

Pdk1

NM_172665

pyruvate dehydrogenase kinase, isoenzyme 1

2.68

0.03

1.96

Me1

NM_001198933

malic enzyme 1, TV 2

2.49

0.03

1.90

Mef2b

NM_001045484

myocyte enhancer factor 2B, TV 2

3.17

0.03

1.88

Foxp2

ENSMUST00000118133

forkhead box P2 [ENSMUST00000118133]

2.08

0.03

1.79

Aurka

NM_011497

aurora kinase A

2.07

0.03

1.70

Ube2e2

NM_144839

ubiquitin-conjugating enzyme E2E 2

3.03

0.03

1.66

Bmpr1a

NM_009758

bone morphogenetic protein receptor, type 1A

3.25

0.04

1.45

Kcnj10

NM_001039484

potassium inwardly-rectifying channel, subfamily J, M 10

-3.04

0.04

1.39

Hfe

NM_010424

hemochromatosis

-2.07

0.04

1.33

Pdss1

NM_019501

prenyl (solanesyl) diphosphate synthase, subunit 1

2.06

0.04

1.07

Hpgd

NM_008278

hydroxyprostaglandin dehydrogenase 15

-2.94

0.04

1.04

Fabp5

NM_010634

fatty acid binding protein 5

2.65

0.04

1.02

Comparison of transcriptoma of c-myc-3’RR/Cdk4R24C and c-myc-3’RR/p53+/- MCL-like lymphomas. Among these 44,000 genes, 176 significantly differed. A Log score >2, a Log ratio >2 or <-2 and a p<0.05 was used as cut of. A: c-myc-3’RR/p53+/- MCL-like lymphomas; B: c-myc-3’RR/Cdk4R24C MCL-like lymphomas; M: member; TV: transcript variant.

 

Differences concerning genes involved in diabetes and obesity (such as Abcc8, Trf, apoc1 and IGF-1) appear directly linked to the Cdk4R24C mutation since loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia [10]. The metabolic and endocrinic changes resulting from diabetes and obesity may dysregulate DNA repair, gene functions and cell mutation rate favouring neoplastic transformation and leading to hematologic malignancy and cancer [11]. For example IGF-1 (insulin growth factor 1) transcripts are markedly elevated in MCL-like lymphomas of c-myc-3’RR/Cdk4R24C mice; IGF-1 involvement being well documented in cancer [11]. Differences concerning genes implicated in the growth and signalling processes could be explained by the Cdk4R24C and p53 mutations themselves. For example, up-regulation of the cell cycle regulatory genes Ccnb1 and Cdc20 in MCL-like lymphomas of c-myc-3’RR/p53+/- mice appear directly linked to the p53+/- mutation that increases the rate and occurrence of c-myc-induced lymphomas [6, 12]. Indeed, Ccnb1 overexpression in lymphomas is caused by non-functional p53 [13], while Cdc20 is negatively regulated by p53 [14]. In turn the down regulation of the Cdk4 inhibitor Cdkn2a in MCL-like lymphomas of c-myc-3’RR/Cdk4R24C mice appears related to its inefficiency in Cdk4R24C mice. As a consequence of a higher proliferation rate, several genes implicated in cell metabolism (such as Adarb1, Lmo1, AK4, Slc2a4) and nuclear membrane or chromosome stability (such as Lmnb1 and Cenpi) are higher in MCL-like lymphomas of c-myc-3’RR/p53+/- mice than in MCL-like lymphomas of c-myc-3’RR/Cdk4R24C mice. Finally and also linked to a higher rate of proliferation, several differences are found concerning genes implicated in cellular architecture especially on the actin and microtubule cytoskeletons (such as advillin Kif18b, Mtus2, Tubb2b, Mtap2, Stmn1), key players that underpin growth processes [15].

Table 3: Genes implicated in cellular architecture.

Log2
ratio

 p-value

log score

Name

Systematic
Name

Description

A-B

A-B

A-B

Ahnak

NM_001039959

nucleoprotein (desmoyokin), TV 3

-4.48

0.03

3.95

Myadm

NM_016969

myeloid-associated differentiation marker, TV 4

-5.5

0.03

3.69

Stab2

NM_138673

stabilin 2

-3.39

0.03

3.50

Fcna

NM_007995

ficolin A

-4.8

0.03

3.46

Avil

NM_009635

advillin

4.05

0.03

3.42

Ctnnbip1

NM_023465

catenin beta interacting protein 1, TV 1

2.32

0.03

2.85

Ncan

NM_007789

neurocan

2.23

0.03

2.78

Kif18b

NM_197959

kinesin family member 18B

2.17

0.03

2.68

Pcolce2

NM_029620

procollagen C-endopeptidase enhancer 2

-2.11

0.03

2.61

Spock2

NM_052994

sparc/osteonectin

2.36

0.03

2.50

Thbs3

NM_013691

thrombospondin 3

-4.07

0.03

2.37

Lmnb1

NM_010721

lamin B1

2.01

0.03

2.30

Zwilch

NM_026507

Zwilch, kinetochore associated

2.25

0.03

2.19

Cd97

NM_011925

CD97 antigen, TV 1

-3.62

0.03

2.07

Mtus2

NM_029920

microtubule associated tumor suppressor candidate 2

-4.03

0.03

1.95

Cenpi

NM_145924

centromere protein I

2.11

0.03

1.94

Mef2b

NM_001045484

myocyte enhancer factor 2B, TV 2

3.17

0.03

1.88

Dscaml1

NM_001081270

down syndrome cell adhesion molecule-like 1

-2.58

0.03

1.81

Tubb2b

NM_023716

tubulin, beta 2B

-4.58

0.03

1.75

Spc25

NM_001199123

NDC80 kinetochore complex component, TV 1

2.23

0.04

1.56

Mtap2

NM_001039934

microtubule-associated protein 2, TV 1

2.24

0.04

1.56

Stmn1

NM_019641

stathmin 1

2.77

0.04

1.39

Slmo1

NM_144867

slowmo homolog 1

4.5

0.04

1.17

Comparison of transcriptoma of c-myc-3’RR/Cdk4R24C and c-myc-3’RR/p53+/- MCL-like lymphomas. Among these 44,000 genes, 176 significantly differed. A Log score >2, a Log ratio >2 or <-2 and a p<0.05 was used as cut of. A: c-myc-3’RR/p53+/- MCL-like lymphomas; B: c-myc-3’RR/Cdk4R24C MCL-like lymphomas; M: member; TV: transcript variant.

 

MCL-like lymphomas of c-myc-3’RR/p53+/- mice are more aggressive than those of c-myc-3’RR/Cdk4R24C mice despite similar flow cytometry profiles [5, 6]. Comparison of their gene expression profiles explains this difference by a marked overexpression of several cell cycle regulatory genes. Gene expression profiles do not highlight other specific differences other than those in relation with their specific mutational status (i.e., Cdk4R24C or p53 mutations). We propose that similarly to typical human MCL and its blastoid or cyclin-D1 variants that correspond to the same genetic entity [1], MCL-like lymphomas of c-myc-3’RR/p53+/- mice and c-myc-3’RR/Cdk4R24C mice represent a spectrum of the same entity. Our results indicate that deregulation of two different signalling pathways within a single B cell entity can lead to the emergence of a unique lymphoma phenotype carrying different oncogenic stigmas. These different oncogenic stigmas explain differences concerning the proliferative and/or apoptotic status of the lymphoma and thus potential differential responses to treatment. Tumor transcriptoma analysis and tumor DNA sequence analysis could thus become useful laboratory tests paving the way towards personalized treatments [16].

Table 4: Unknown genes.

Log2
ratio

 p-value

log score

Name

Systematic
Name

Description

A-B

A-B

A-B

Pqlc1

NM_001164420

PQ loop repeat containing 1, TV 2

-3.62

0.03

3.97

NAP101497-1

same

unknown

-2.54

0.03

3.09

LOC100502767

XR_104684

hypothetical LOC100502767

3.01

0.03

3.04

A_55_P1973560

same

unknown

2.29

0.03

2.99

Ng23

NM_023893

Ng23 protein

4.68

0.03

2.92

A_55_P2137023

same

unknown

2.64

0.03

2.87

ENSMUST00000103452

same

predicted gene 16886

-2.55

0.03

2.75

Frmd5

NM_172673

FERM domain containing 5

2.51

0.03

2.56

4931429I11Rik

NM_001081121

RIKEN cDNA 4931429I11 gene

-4.04

0.03

2.46

5730416F02Rik

NR_033596

RIKEN cDNA 5730416F02 gene

-2.66

0.03

2.28

ENSMUST00000098678

same

RIKEN cDNA D930028M14 gene

-2.44

0.03

2.16

ENSMUST00000103381

same

predicted gene 16944

-2.54

0.03

2.15

ENSMUST00000103341

same

predicted gene 16729

-5.03

0.03

2.00

Clip3

NM_001081114

CAP-GLY domain containing linker protein 3

3.96

0.03

1.89

ENSMUST00000103314

same

predicted gene 16798

-4.33

0.03

1.80

ENSMUST00000103348

same

predicted gene 1502

-4.52

0.03

1.76

Cd2

NM_013486

CD2 antigen

-2.97

0.03

1.72

9030409G11Rik

NM_001109685

RIKEN cDNA 9030409G11 gene, TV 3

2.64

0.03

1.69

ENSMUST00000103444

same

predicted gene 16971

-2.46

0.03

1.69

Lrrc23

NM_013588

leucine rich repeat containing 23

-3.82

0.03

1.67

Sssca1

NM_020491

Sjogren's syndrome/scleroderma autoantigen 1 homolog

2.06

0.04

1.64

ENSMUST00000103316

same

predicted gene 5571

-3.83

0.04

1.59

Gm3227

XR_105936

predicted gene 3227

-2.99

0.04

1.46

C77080

NM_001033189

expressed sequence C77080

-3.6

0.04

1.44

2810025M15Rik

NR_027984

RIKEN cDNA 2810025M15 gene

2.05

0.04

1.25

2200002J24Rik

NM_026961

RIKEN cDNA 2200002J24 gene

2.24

0.04

1.25

6030419C18Rik

NM_176921

RIKEN cDNA 6030419C18 gene

2.42

0.04

1.20

ENSMUST00000103493

same

predicted gene 16694

-2.37

0.04

1.16

A_55_P2040519

A_55_P2040519

unknown

2.63

0.04

1.14

A_55_P2121294

same

unknown

-2.46

0.04

1.12

D330028D13Rik

NM_172727

RIKEN cDNA D330028D13 gene, TV 1

2.05

0.04

1.11

LOC100502627

BC058714

cDNA clone IMAGE:6842867

2.26

0.04

1.01

Comparison of transcriptoma of c-myc-3’RR/Cdk4R24C and c-myc-3’RR/p53+/- MCL-like lymphomas. Among these 44,000 genes, 176 significantly differed. A Log score >2, a Log ratio >2 or <-2 and a p<0.05 was used as cut of. A: c-myc-3’RR/p53+/- MCL-like lymphomas; B: c-myc-3’RR/Cdk4R24C MCL-like lymphomas; M: member; TV: transcript variant.

 

Acknowledgments

We acknowledge the technological expertise of the Nice Sophia-Antipolis Functional Genomics Platform. The authors thank Pascal Barbry for helpful discussions and support during this work.

Grant support

This work was supported by grants from Ligue Contre le Cancer (comité départemental de la Haute-Vienne, Creuse, Corrèze, Gironde et Landes), Comité d’Organisation sur la Recherche sur le Cancer en Limousin, Conseil Régional du Limousin, and ANR (Projets Blanc 2011). C. Vincent-Fabert was supported by a grant from the Association pour la Recherche sur le Cancer (ARC). P. Dubus were supported by grants from the Région Aquitaine. The Nice Sophia-Antipolis Functional Genomics Platform was supported by MICROENVIMET, FP7-HEALTHF2-2008-201279, the ARC, and the INCa.

Conflict of interest

None

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