Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2013

Open Access 01-12-2013 | Primary research

HOXB1 restored expression promotes apoptosis and differentiation in the HL60 leukemic cell line

Authors: Marina Petrini, Federica Felicetti, Lisabianca Bottero, Maria Cristina Errico, Ornella Morsilli, Alessandra Boe, Alessandra De Feo, Alessandra Carè

Published in: Cancer Cell International | Issue 1/2013

Login to get access

Abstract

Background

Homeobox (HOX) genes deregulation has been largely implicated in the development of human leukemia. Among the HOXB cluster, HOXB1 was silent in a number of analyzed acute myeloid leukemia (AML) primary cells and cell lines, whereas it was expressed in normal terminally differentiated peripheral blood cells.

Methods

We evaluated the biological effects and the transcriptome changes determined by the retroviral transduction of HOXB1 in the human promyelocytic cell line HL60.

Results

Our results suggest that the enforced expression of HOXB1 reduces cell growth proliferation, inducing apoptosis and cell differentiation along the monocytic and granulocytic lineages. Accordingly, gene expression analysis showed the HOXB1-dependent down-regulation of some tumor promoting genes, paralleled by the up-regulation of apoptosis- and differentiation-related genes, thus supporting a tumor suppressor role for HOXB1 in AML. Finally, we indicated HOXB1 promoter hypermethylation as a mechanism responsible for HOXB1 silencing.

Conclusions

We propose HOXB1 as an additional member of the HOX family with tumour suppressor properties suggesting a HOXB1/ATRA combination as a possible future therapeutic strategy in AML.
Appendix
Available only for authorised users
Literature
1.
Garcia-Fernandez J: The genesis and evolution of homeobox gene clusters. Nat Rev Genet. 2005, 6: 881-892.CrossRefPubMed
2.
Scott MP: Vertebrate homeobox gene nomenclature. Cell. 1992, 71: 551-553. 10.1016/0092-8674(92)90588-4.CrossRefPubMed
3.
Krumlauf R: Hox genes in vertebrate development. Cell. 1994, 78: 1991-2011.CrossRef
4.
Eklund EA: The role of hox proteins in leukemogenesis; insights into key regulatory events in hematopoiesis. Crit Rev Oncog. 2011, 16: 65-76. 10.1615/CritRevOncog.v16.i1-2.70.PubMedCentralCrossRefPubMed
5.
Giampaolo A, Sterpetti P, Bulgarini D, Samoggia P, Pelosi E, Valtieri M, Peschle C: Key functional role and lineage-specific expression of selected HOXB genes in purified haematopoietic progenitor differentiation. Blood. 1994, 84: 3637-3647.PubMed
6.
Sauvageau G, Lansdorp PM, Eaves CJ, Hogge DE, Dragowska WH, Reid DS, Largman C, Lawrence HJ, Hunphries RK: Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells. Proc Natl Acad Sci USA. 1994, 91: 12223-12227. 10.1073/pnas.91.25.12223.PubMedCentralCrossRefPubMed
7.
Carè A, Testa U, Bassani A, Tritarelli E, Montesoro E, Samoggia P, Cianetti L, Peschle C: Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes. Mol Cell Biol. 1994, 14: 4872-4877.PubMedCentralCrossRefPubMed
8.
Sauvageau G, Thorsteinsdottir U, Eaves CJ, Lawrence HJ, Largman C, Lansdorp PM, Humphries RK: Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 1995, 9: 1753-1765. 10.1101/gad.9.14.1753.CrossRefPubMed
9.
Giampaolo A, Felli N, Diverio D, Morsilli O, Samoggia P, Breccia M, Lo Coco F, Peschle C, Testa U: Expression pattern of HOXB6 homeobox gene in myelomonocytic differentiation and acute myeloid leukaemia. Leukaemia. 2002, 16: 1293-1301. 10.1038/sj.leu.2402532.CrossRef
10.
Gough SM, Slape CI, Aplan PD: NUP98 gene fusions and hematopoietic malignancies: common themes and new biological insights. Blood. 2011, 118: 6247-6257. 10.1182/blood-2011-07-328880.PubMedCentralCrossRefPubMed
11.
Yan-Fang T, Dong W, Li P, Wen-Li Z, Jun L, Na W, Jian W, Xing F, Yan-Hong L, Jian N, Jian P: Analyzing the gene expression profile of pediatric acute myeloid leukemia with real-time PCR arrays. Cancer Cell Int. 2012, 12: 40-51. 10.1186/1475-2867-12-40.PubMedCentralCrossRefPubMed
12.
Raman V, Martensen SA, Reisman D, Evron E, Odenwald WF, Jaffee E, Marks J, Sukumar S: Compromised. HOXA5 function can limit p53 expression in human breast tumours. Nature. 2000, 405: 974-978. 10.1038/35016125.CrossRefPubMed
13.
Chen H, Chung S, Sukumar S: HOXA5- induced apoptosis in breast cancer cells is mediated by caspase2 and 8. Mol Cell Biol. 2004, 24: 924-935. 10.1128/MCB.24.2.924-935.2004.PubMedCentralCrossRefPubMed
14.
Strathdee G, Sim A, Soutar R, Holyoake TL, Brown R: HOXA5 is targeted by cell – type specific CpG island methylation in normal cells and during the development of acute myeloid leukemia. Carcinogenesis. 2007, 28: 299-309.CrossRefPubMed
15.
Duong CV, Emes RD, Wessely F, Yacqub-Usman K, Clayton RN, Farrell WE: Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas. Endocr Relat Cancer. 2012, 19: 805-816. 10.1530/ERC-12-0251.CrossRefPubMed
16.
Celetti A, Barba P, Cillo C, Rotoli B, Boncinelli E, Magli MC: Characteristic patterns of HOX gene expression in different types of human leukemia. Int J Cancer. 1993, 53: 237-244. 10.1002/ijc.2910530211.CrossRefPubMed
17.
Oki Y, Issa JP: Epigenetic mechanisms in AML-a target for therapy. Cancer Treat Res. 2010, 145: 19-40.CrossRefPubMed
18.
Montesoro E, Castelli G, Morsilli O, Nisini R, Stafsnes MH, Carè A, Peschle C, Chelucci C: Unilineage monocytopoiesis in hematopoietic progenitor culture: switching cytokine treatment at all Mo developmental stages induces differentiation into dendritic cells. Cell Death Differ. 2006, 13: 250-259. 10.1038/sj.cdd.4401748.CrossRefPubMed
19.
Felicetti F, Bottero L, Felli N, Mattia G, Labbaye C, Alvino E, Peschle C, Colombo MP, Carè A: Role of PLZF in melanoma progression. Oncogene. 2004, 3: 4567-4576.CrossRef
20.
Baird A, Coimbra R, Dang X, Lopez N, Lee J, Krzyzaniak M, Winfield R, Potenza B, Eliceiri BP: Cell surface localization and release of the candidate tumor suppressor Ecrg4 from polymorphonuclear cells and monocytes activate macrophages. J Leukoc Biol. 2012, 91: 773-781. 10.1189/jlb.1011503.PubMedCentralCrossRefPubMed
21.
Pufahl L, Katryniok C, Schnur N, Sorg BL, Metzner J, Grez M, Steinhilber D: Trichostatin A induces 5-lipoxygenase promoter activity and mRNA expression via inhibition of histone deacetylase 2 and 3. J Cell Mol Med. 2012, 16: 1461-1473. 10.1111/j.1582-4934.2011.01420.x.PubMedCentralCrossRefPubMed
22.
Shah S, Sukumar N: The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010, 10: 361-371. 10.1038/nrc2826.CrossRefPubMed
23.
Asatiani E, Huang WX, Wang A, Rodriguez Ortner E, Cavalli LR, Haddad BR, Gelmann EP: Deletion, methylation, and expression of the NKX3.1. Cancer Res. 2005, 65: 1164-1173. 10.1158/0008-5472.CAN-04-2688.CrossRefPubMed
24.
Carrio M, Arderiu G, Myers C, Boudreau NJ: Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model. Cancer Res. 2005, 65: 7177-7185. 10.1158/0008-5472.CAN-04-1717.CrossRefPubMed
25.
Wang L, Chen S, Xue M, Zhong J, Wang X, Gan L, Lam EK, Liu X, Zhang J, Zhou T, Yu J, Jin H, Si J: Homeobox D10 gene, a candidate tumor suppressor, is downregulated through promoter hypermethylation and associated with gastric carcinogenesis. Mol Med. 2012, 18: 389-400.PubMedCentralPubMed
26.
Strathdee G, Holyoake TL, Sim A, Parker A, Oscier DG, Melo JV, Meyer S, Eden T, Dickinson AM, Mountford JC, Jorgensen HG, Soutar R, Brown R: Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis. Clin Cancer Res. 2007, 13: 5048-5055. 10.1158/1078-0432.CCR-07-0919.CrossRefPubMed
27.
Lassus P, Araya XO, Lazebnik Y: Requirement for caspase 2 in stress induced apoptosis before mitochondrial permeabilization. Science. 2002, 297: 1352-1354. 10.1126/science.1074721.CrossRefPubMed
28.
Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ: Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science. 2000, 288: 870-874. 10.1126/science.288.5467.870.CrossRefPubMed
29.
Busch CR, Heat DD, Hubberstey A: Sensitive genetic biomarkers for determining apoptosis in the brown bullhead (Ameiurus nebulosus). Gene. 2004, 329: 1-10.CrossRefPubMed
30.
Yang M, Cao X, Yu MC, Gu JF, Shen ZH, Ding M, de Yu B, Zheng S, Liu X: Potent antitumor efficacy of ST13 for colorectal cancer mediated by oncolytic adenovirus via mitochondrial apoptotic cell death. Hum Gene Ther. 2008, 19: 343-353. 10.1089/hum.2007.0137.CrossRefPubMed
31.
Bhoopathi P, Chetty C, Gujrati M, Dinh DH, Rao JS, Lakka S: Cathepsin B facilitates autophagy-mediated apoptosis in SPARC overexpressed primitive neuroectodermal tumor cells. Cell Death Differ. 2010, 17: 1529-1539. 10.1038/cdd.2010.28.PubMedCentralCrossRefPubMed
32.
Di Martino JF, Lacayo NJ, Varadi M, Li L, Saraiya C, Ravindranath Y, Yu R, Sikic BI, Raimondi SC, Dahl GV: Low or absent SPARC expression in acute myeloid leukemia with MLL rearrangements is associated with sensitivity to growth inhibition by exogenous SPARC protein. Leukemia. 2006, 20: 426-432. 10.1038/sj.leu.2404102.CrossRef
33.
Franklin EE, Robertson J: Requirement of Apaf-1 for mitochondrial events and the cleavage or activation of all procaspases during genotoxic stress-induced apoptosis. Biochem J. 2007, 405: 115-122.PubMedCentralCrossRefPubMed
34.
Germain M, Milburn J, Duronio V: MCL-1 inhibits BAX in the absence of MCL-1/BAX Interaction. J Biol Chem. 2008, 283: 6384-6392. 10.1074/jbc.M707762200.CrossRefPubMed
35.
Yu H, Zou Y, Jiang L, Yin Q, He X, Chen L, Zhang Z, Gu W, Li Y: Induction of apoptosis in non-small cell lung cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPA/siRNA complex nanoparticles. Biomaterials. 2013, 34: 2738-2747. 10.1016/j.biomaterials.2012.12.042.CrossRefPubMed
36.
Qin JJ, Nag S, Voruganti S, Wang W, Zhang R: Natural product MDM2 inhibitors: anticancer activity and mechanisms of action. Curr Med Chem. 2012, 19: 5705-5725. 10.2174/092986712803988910.CrossRefPubMed
37.
Jung SY, Jeon HK, Choi JS, Kim YJ: Reduced expression of FASN through SREBP-1 down-regulation is responsible for hypoxic cell death in HepG2 cells. J Cell Biochem. 2012, 113: 3730-3739. 10.1002/jcb.24247.CrossRefPubMed
38.
Turrado C, Puig T, García-Cárceles J, Artola M, Benhamú B, Ortega-Gutiérrez S, Relat J, Oliveras G, Blancafort A, Haro D, Marrero PF, Colomer R, López-Rodríguez ML: New synthetic inhibitors of fatty acid synthase with anticancer activity. J Med Chem. 2012, 55: 5013-5023. 10.1021/jm2016045.CrossRefPubMed
39.
Hole PS, Darley RL, Tonks A: Do reactive oxygen species play a role in myeloid leukemias?. Blood. 2011, 117: 5816-5826. 10.1182/blood-2011-01-326025.CrossRefPubMed
40.
Chen KS, Hsiao YC, Kuo DY, Chou MC, Chu SC, Hsieh YS, Lin TH: Tannic acid-induced apoptosis and enhanced sensitivity to arsenic trioxide in human leukemia HL-60 cells. Leuk Res. 2009, 33: 297-307. 10.1016/j.leukres.2008.08.006.CrossRefPubMed
41.
Cai Y, Qiu S, Gao X, Gu SZ, Liu ZJ: iASPP inhibits p53-independent apoptosis by inhibiting transcriptional activity of p63/p73 on promoters of proapoptotic genes. Apoptosis. 2012, 17: 777-783. 10.1007/s10495-012-0728-z.CrossRefPubMed
42.
Ferretti E, Li B, Zewdu R, Wells V, Hebert JM, Karner C, Anderson MJ, Williams T, Dixon J, Dixon MJ, Depew MJ, Selleri L: A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis. Dev Cell. 2011, 21: 627-641. 10.1016/j.devcel.2011.08.005.PubMedCentralCrossRefPubMed
43.
Adamson ED, Mercola D: Egr1 transcription factor: multiple roles in prostate tumor cell growth and survival. Tumour Biol. 2002, 23: 93-102. 10.1159/000059711.CrossRefPubMed
44.
Zheng L, Pu J, Jiang G, Weng M, He J, Mei H, Hou X, Tong Q: Abnormal expression of early growth response 1 in gastric cancer: association with tumor invasion, metastasis and heparanase transcription. Pathol Int. 2010, 60: 268-277. 10.1111/j.1440-1827.2010.02512.x.CrossRefPubMed
45.
Staber PB, Linkesch W, Zauner D, Beham-Schmid C, Guelly C, Schauer S, Sill H, Hoefler G: Common alterations in gene expression and increased proliferation in recurrent acute myeloid leukemia. Oncogene. 2004, 23: 894-904. 10.1038/sj.onc.1207192.CrossRefPubMed
46.
Ogura T, Evans RM: Evidence for two distinct retinoic acid response pathways for HOXB1 gene regulation. Proc Natl Acad Sci USA. 1995, 17: 392-396.CrossRef
47.
Karpf AR, Jones DA: Reactivating the expression of methylation silenced genes in human cancer. Oncogene. 2002, 21: 5496-5503. 10.1038/sj.onc.1205602.CrossRefPubMed
48.
Claus R, Almstedt M, Lübbert M: Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents. Semin Oncol. 2005, 32: 511-520. 10.1053/j.seminoncol.2005.07.024.CrossRefPubMed
Metadata
Title
HOXB1 restored expression promotes apoptosis and differentiation in the HL60 leukemic cell line
Authors
Marina Petrini
Federica Felicetti
Lisabianca Bottero
Maria Cristina Errico
Ornella Morsilli
Alessandra Boe
Alessandra De Feo
Alessandra Carè
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2013
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-13-101

Other articles of this Issue 1/2013

Cancer Cell International 1/2013 Go to the issue

Primary research

TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells

Primary research

Depleting NFAT1 expression inhibits the ability of invasion and migration of human lung cancer cells

Primary research

Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations

Primary research

Anti-cancer effects of ginsenoside compound k on pediatric acute myeloid leukemia cells

Primary research

The effects of a histone deacetylase inhibitor on biological behavior of diffuse large B-cell lymphoma cell lines and insights into the underlying mechanisms

Primary research

The mitochondrial C16069T polymorphism, not mitochondrial D310 (D-loop) mononucleotide sequence variations, is associated with bladder cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits