Functional analysis of the two reciprocal fusion genes MLL-NEBL and NEBL-MLL reveal their oncogenic potential

被引：22

作者：

Emerenciano, Mariana ^{[1
,2
]}

Kowarz, Eric ^{[2
]}

Karl, Katharina ^{[2
]}

Lopes, Bruno de Almeida ^{[1
]}

Scholz, Bastian ^{[2
]}

Bracharz, Silvia ^{[2
]}

Meyer, Claus ^{[2
]}

Pombo-de-Oliveira, Maria S. ^{[1
]}

Marschalek, Rolf ^{[2
]}

机构：

[1] Natl Canc Inst, Res Ctr, Pediat Hematol Oncol Program, Rio De Janeiro, Brazil

[2] Goethe Univ Frankfurt, Inst Pharmaceut Biol, ZAFES, D-60438 Frankfurt, Germany

来源：

CANCER LETTERS | 2013年 / 332卷 / 01期

关键词：

MLL; NEBL; Infant leukemia; LEUKEMIC TRANSFORMATION; MYELOID PROGENITORS; LIM-NEBULETTE; PROTEINS; MICE; AF4;

D O I：

10.1016/j.canlet.2012.12.023

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

MLL gene aberrations are frequently diagnosed in infant acute myeloid leukemia (AML). We previously described the MLL-NEBL and NEBL-MLL genomic fusions in an infant AML patient with a chromosomal translocation t(10;11)(p12;q23). NEBL was the second Nebulin family member (LASP1, NEBL) which was found to be involved in MLL rearrangements. Here, we report on our attempts to unravel the oncogenic properties of both fusion genes. First, RT-PCR analyses revealed the presence of the MLL-NEBL and NEBL-MLL mRNAs in the diagnostic sample of the patient. Next, expression cassettes for MLL-NEBL and NEBL-MLL were cloned into a sleeping beauty vector backbone. After stable transfection, the biological effects of MLL-NEBL, NEBL-MLL or the combination of both fusion proteins were investigated in a conditional cell culture model. NEBL-MLL but also co-transfected cells displayed significantly higher growth rates according to the data obtained by cell proliferation assay. The focus formation experiments revealed differences in the shape and number of colonies when comparing MLL-NEBL, NEBL-MLL- and co-transfected cells. The results obtained in this study suggest that the reciprocal fusion genes of the Nebulin gene family might be of biological importance. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

引用

页码：30 / 34

页数：5

共 16 条

[1] Interaction of AF4 wild-type and AF4. MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology? [J].

Bursen, A ;

Moritz, S ;

Gaussmann, A ;

Moritz, S ;

Dingermann, T ;

Marschalek, R .

ONCOGENE, 2004, 23 (37) :6237-6249

[2] The AF4.MLL fusion protein is capable of inducing ALL in mice without requirement of MLL.AF4 [J].

Bursen, Adelheid ;

Schwabe, Karen ;

Ruester, Brigitte ;

Henschler, Reinhard ;

Ruthardt, Martin ;

Dingermann, Theo ;

Marschalek, Rolf .

BLOOD, 2010, 115 (17) :3570-3579

[3] An MII-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: A method to create fusion oncogenes [J].

Corral, J ;

Lavenir, I ;

Impey, H ;

Warren, AJ ;

Forster, A ;

Larson, TA ;

Bell, S ;

McKenzie, ANJ ;

King, G ;

Rabbitts, TH .

CELL, 1996, 85 (06) :853-861

[4] Nebulette is the second member of the nebulin family fused to the MLL gene in infant leukemia [J].

Coser, Virginia M. ;

Meyer, Claus ;

Basegio, Rosania ;

Menezes, Juliane ;

Marschalek, Rolf ;

Pombo-de-Oliveira, Maria S. .

CANCER GENETICS AND CYTOGENETICS, 2010, 198 (02) :151-154

[5] Ectopic expression of LIM-nebulette (LASP2) reveals roles in cell migration and spreading [J].

Deng, Xiaodi A. ;

Norris, Andrea ;

Panaviene, Zivile ;

Moncman, Carole L. .

CELL MOTILITY AND THE CYTOSKELETON, 2008, 65 (10) :827-840

[6] The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10 [J].

DiMartino, JF ;

Ayton, PM ;

Chen, EH ;

Naftzger, CC ;

Young, BD ;

Cleary, ML .

BLOOD, 2002, 99 (10) :3780-3785

[7] Combined effects of the two reciprocal t(4; II) fusion proteins MLL . AF4 and AF4 . MLL confer resistance to apoptosis, cell cycling capacity and growth transformation [J].

Gaussmann, A. ;

Wenger, T. ;

Eberle, I. ;

Bursen, A. ;

Bracharz, S. ;

Herr, I. ;

Dingermann, T. ;

Marschalek, R. .

ONCOGENE, 2007, 26 (23) :3352-3363

[8]

Katoh M, 2003, INT J MOL MED, V12, P405

[9] H3K79 Methylation Profiles Define Murine and Human MLL-AF4 Leukemias [J].

Krivtsov, Andrei V. ;

Feng, Zhaohui ;

Lemieux, Madeleine E. ;

Faber, Joerg ;

Vempati, Sridhar ;

Sinha, Amit U. ;

Xia, Xiaobo ;

Jesneck, Jonathan ;

Bracken, Adrian P. ;

Silverman, Lewis B. ;

Kutok, Jeffery L. ;

Kung, Andrew L. ;

Armstrong, Scott A. .

CANCER CELL, 2008, 14 (05) :355-368

[10] Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice [J].

Lavau, C ;

Luo, RT ;

Du, CC ;

Thirman, MJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (20) :10984-10989

← 1 2 →