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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2011 | Research

MEIS1, PREP1, and PBX4 Are Differentially Expressed in Acute Lymphoblastic Leukemia: Association of MEIS1 Expression with Higher Proliferation and Chemotherapy Resistance

Authors: Judith A Rosales-Aviña, Jorge Torres-Flores, Adriana Aguilar-Lemarroy, Carmen Gurrola-Díaz, Georgina Hernández-Flores, Pablo C Ortiz-Lazareno, José M Lerma-Díaz, Ruth de Celis, Óscar González-Ramella, Esperanza Barrera-Chaires, Alejandro Bravo-Cuellar, Luis F Jave-Suárez

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2011

Abstract

Background

The Three-amino acid-loop-extension (TALE) superfamily of homeodomain-containing transcription factors have been implicated in normal hematopoiesis and in leukemogenesis and are important survival, differentiation, and apoptosis pathway modulators. In this work, we determined the expression levels of TALE genes in leukemic-derived cell lines, in blood samples of patients with Acute lymphoblastic leukemia (ALL), and in the blood samples of healthy donors.

Results

Here we show increased expression of MEIS1, MEIS2, and PREP1 genes in leukemia-derived cell lines compared with blood normal cells. High levels of MEIS1 and PREP1, and low levels of PBX4 expression were also founded in samples of patients with ALL. Importantly, silencing of MEIS1 decreases the proliferation of leukemia-derived cells but increases their survival after etoposide treatment. Etoposide-induced apoptosis induces down-regulation of MEIS1 expression or PREP1 up-regulation in chemotherapy-resistant cells.

Conclusions

Our results indicate that up-regulation of MEIS1 is important for sustaining proliferation of leukemic cells and that down-regulation of MEIS1 or up-regulation of PREP1 and PBX genes could be implicated in the modulation of the cellular response to chemotherapeutic-induced apoptosis.

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Burglin TR: Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res. 1997, 25: 4173-4180. 10.1093/nar/25.21.4173.PubMedCentralCrossRefPubMed

Fognani C, Kilstrup-Nielsen C, Berthelsen J, Ferretti E, Zappavigna V, Blasi F: Characterization of PREP2, a paralog of PREP1, which defines a novel sub-family of the MEINOX TALE homeodomain transcription factors. Nucleic Acids Res. 2002, 30: 2043-2051. 10.1093/nar/30.9.2043.PubMedCentralCrossRefPubMed

Monica K, Galili N, Nourse J, Saltman D, Cleary ML: PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Mol Cell Biol. 1991, 11: 6149-6157.PubMedCentralCrossRefPubMed

Wagner K, Mincheva A, Korn B, Lichter P, Popperl H: Pbx4, a new Pbx family member on mouse chromosome 8, is expressed during spermatogenesis. Mech Dev. 2001, 103: 127-131. 10.1016/S0925-4773(01)00349-5.CrossRefPubMed

Di Giacomo G, Koss M, Capellini TD, Brendolan A, Popperl H, Selleri L: Spatio-temporal expression of Pbx3 during mouse organogenesis. Gene Expr Patterns. 2006, 6: 747-757. 10.1016/j.modgep.2005.12.002.CrossRefPubMed

Selleri L, Depew MJ, Jacobs Y, Chanda SK, Tsang KY, Cheah KS, Rubenstein JL, O'Gorman S, Cleary ML: Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development. 2001, 128: 3543-3557.PubMed

Toresson H, Parmar M, Campbell K: Expression of Meis and Pbx genes and their protein products in the developing telencephalon: implications for regional differentiation. Mech Dev. 2000, 94: 183-187. 10.1016/S0925-4773(00)00324-5.CrossRefPubMed

DiMartino JF, Selleri L, Traver D, Firpo MT, Rhee J, Warnke R, O'Gorman S, Weissman IL, Cleary ML: The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. Blood. 2001, 98: 618-626. 10.1182/blood.V98.3.618.CrossRefPubMed

Pillay LM, Forrester AM, Erickson T, Berman JN, Waskiewicz AJ: The Hox cofactors Meis1 and Pbx act upstream of gata1 to regulate primitive hematopoiesis. Dev Biol. 2010

10.

Hisa T, Spence SE, Rachel RA, Fujita M, Nakamura T, Ward JM, Devor-Henneman DE, Saiki Y, Kutsuna H, Tessarollo L, et al: Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. EMBO J. 2004, 23: 450-459. 10.1038/sj.emboj.7600038.PubMedCentralCrossRefPubMed

11.

Moskow JJ, Bullrich F, Huebner K, Daar IO, Buchberg AM: Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol. 1995, 15: 5434-5443.PubMedCentralCrossRefPubMed

12.

Nakamura T, Largaespada DA, Shaughnessy JD, Jenkins NA, Copeland NG: Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias. Nat Genet. 1996, 12: 149-153. 10.1038/ng0296-149.CrossRefPubMed

13.

Calvo KR, Knoepfler PS, Sykes DB, Pasillas MP, Kamps MP: Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia. Proc Natl Acad Sci USA. 2001, 98: 13120-13125. 10.1073/pnas.231115398.PubMedCentralCrossRefPubMed

14.

Diaz-Blanco E, Bruns I, Neumann F, Fischer JC, Graef T, Rosskopf M, Brors B, Pechtel S, Bork S, Koch A, et al: Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase. Leukemia. 2007, 21: 494-504. 10.1038/sj.leu.2404549.CrossRefPubMed

15.

Mann RS, Affolter M: Hox proteins meet more partners. Curr Opin Genet Dev. 1998, 8: 423-429. 10.1016/S0959-437X(98)80113-5.CrossRefPubMed

16.

Moens CB, Selleri L: Hox cofactors in vertebrate development. Dev Biol. 2006, 291: 193-206. 10.1016/j.ydbio.2005.10.032.CrossRefPubMed

17.

Chung EY, Liu J, Homma Y, Zhang Y, Brendolan A, Saggese M, Han J, Silverstein R, Selleri L, Ma X: Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1. Immunity. 2007, 27: 952-964. 10.1016/j.immuni.2007.11.014.PubMedCentralCrossRefPubMed

18.

Deflorian G, Tiso N, Ferretti E, Meyer D, Blasi F, Bortolussi M, Argenton F: Prep1.1 has essential genetic functions in hindbrain development and cranial neural crest cell differentiation. Development. 2004, 131: 613-627. 10.1242/dev.00948.CrossRefPubMed

19.

Penkov D, Di Rosa P, Fernandez Diaz L, Basso V, Ferretti E, Grassi F, Mondino A, Blasi F: Involvement of Prep1 in the alphabeta T-cell receptor T-lymphocytic potential of hematopoietic precursors. Mol Cell Biol. 2005, 25: 10768-10781. 10.1128/MCB.25.24.10768-10781.2005.PubMedCentralCrossRefPubMed

20.

Ferretti E, Villaescusa JC, Di Rosa P, Fernandez-Diaz LC, Longobardi E, Mazzieri R, Miccio A, Micali N, Selleri L, Ferrari G, Blasi F: Hypomorphic mutation of the TALE gene Prep1 (pKnox1) causes a major reduction of Pbx and Meis proteins and a pleiotropic embryonic phenotype. Mol Cell Biol. 2006, 26: 5650-5662. 10.1128/MCB.00313-06.PubMedCentralCrossRefPubMed

21.

Roschke AV, Tonon G, Gehlhaus KS, McTyre N, Bussey KJ, Lababidi S, Scudiero DA, Weinstein JN, Kirsch IR: Karyotypic complexity of the NCI-60 drug-screening panel. Cancer Res. 2003, 63: 8634-8647.PubMed

22.

Micali N, Ferrai C, Fernandez-Diaz LC, Blasi F, Crippa MP: Prep1 directly regulates the intrinsic apoptotic pathway by controlling Bcl-XL levels. Mol Cell Biol. 2009, 29: 1143-1151. 10.1128/MCB.01273-08.PubMedCentralCrossRefPubMed

23.

Allen TD, Zhu YX, Hawley TS, Hawley RG: TALE homeoproteins as HOX11-interacting partners in T-cell leukemia. Leuk Lymphoma. 2000, 39: 241-256. 10.3109/10428190009065824.CrossRefPubMed

24.

Kumar AR, Li Q, Hudson WA, Chen W, Sam T, Yao Q, Lund EA, Wu B, Kowal BJ, Kersey JH: A role for MEIS1 in MLL-fusion gene leukemia. Blood. 2009, 113: 1756-1758. 10.1182/blood-2008-06-163287.PubMedCentralCrossRefPubMed

25.

Geerts D, Schilderink N, Jorritsma G, Versteeg R: The role of the MEIS homeobox genes in neuroblastoma. Cancer Lett. 2003, 197: 87-92. 10.1016/S0304-3835(03)00087-9.CrossRefPubMed

26.

Kawagoe H, Humphries RK, Blair A, Sutherland HJ, Hogge DE: Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia. 1999, 13: 687-698. 10.1038/sj.leu.2401410.CrossRefPubMed

27.

Argiropoulos B, Yung E, Humphries RK: Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis. Genes Dev. 2007, 21: 2845-2849. 10.1101/gad.1619407.CrossRefPubMed

28.

Wermuth PJ, Buchberg AM: Meis1-mediated apoptosis is caspase dependent and can be suppressed by coexpression of HoxA9 in murine and human cell lines. Blood. 2005, 105: 1222-1230.CrossRefPubMed

29.

Fujino T, Yamazaki Y, Largaespada DA, Jenkins NA, Copeland NG, Hirokawa K, Nakamura T: Inhibition of myeloid differentiation by Hoxa9, Hoxb8, and Meis homeobox genes. Exp Hematol. 2001, 29: 856-863. 10.1016/S0301-472X(01)00655-5.CrossRefPubMed

30.

Pennartz S, Belvindrah R, Tomiuk S, Zimmer C, Hofmann K, Conradt M, Bosio A, Cremer H: Purification of neuronal precursors from the adult mouse brain: comprehensive gene expression analysis provides new insights into the control of cell migration, differentiation, and homeostasis. Mol Cell Neurosci. 2004, 25: 692-706. 10.1016/j.mcn.2003.12.011.CrossRefPubMed

31.

Smith JE, Afonja O, Yee HT, Inghirami G, Takeshita K: Chromosomal mapping to 15q14 and expression analysis of the human MEIS2 homeobox gene. Mamm Genome. 1997, 8: 951-952. 10.1007/s003359900621.CrossRefPubMed

32.

Ferretti E, Schulz H, Talarico D, Blasi F, Berthelsen J: The PBX-regulating protein PREP1 is present in different PBX-complexed forms in mouse. Mech Dev. 1999, 83: 53-64. 10.1016/S0925-4773(99)00031-3.CrossRefPubMed

33.

Diaz VM, Bachi A, Blasi F: Purification of the Prep1 interactome identifies novel pathways regulated by Prep1. Proteomics. 2007, 7: 2617-2623. 10.1002/pmic.200700197.CrossRefPubMed

34.

Berthelsen J, Zappavigna V, Mavilio F, Blasi F: Prep1, a novel functional partner of Pbx proteins. EMBO J. 1998, 17: 1423-1433. 10.1093/emboj/17.5.1423.PubMedCentralCrossRefPubMed

35.

Longobardi E, Blasi F: Overexpression of PREP-1 in F9 teratocarcinoma cells leads to a functionally relevant increase of PBX-2 by preventing its degradation. J Biol Chem. 2003, 278: 39235-39241. 10.1074/jbc.M304704200.CrossRefPubMed

36.

Micali N, Longobardi E, Iotti G, Ferrai C, Castagnaro L, Ricciardi M, Blasi F, Crippa MP: Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress. Nucleic Acids Res. 2010

37.

Qiu Y, Song B, Zhao G, Deng B, Makino T, Tomita Y, Wang J, Luo W, Doki Y, Aozasa K, Morii E: Expression level of Pre B cell leukemia homeobox 2 correlates with poor prognosis of gastric adenocarcinoma and esophageal squamous cell carcinoma. Int J Oncol. 2010, 36: 651-663.PubMed

38.

Zuckerman V, Wolyniec K, Sionov RV, Haupt S, Haupt Y: Tumour suppression by p53: the importance of apoptosis and cellular senescence. J Pathol. 2009, 219: 3-15.PubMed

Title: MEIS1, PREP1, and PBX4 Are Differentially Expressed in Acute Lymphoblastic Leukemia: Association of MEIS1 Expression with Higher Proliferation and Chemotherapy Resistance
Authors: Judith A Rosales-Aviña
Jorge Torres-Flores
Adriana Aguilar-Lemarroy
Carmen Gurrola-Díaz
Georgina Hernández-Flores
Pablo C Ortiz-Lazareno
José M Lerma-Díaz
Ruth de Celis
Óscar González-Ramella
Esperanza Barrera-Chaires
Alejandro Bravo-Cuellar
Luis F Jave-Suárez
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2011
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/1756-9966-30-112

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