Co‑existence of PHF6 and NOTCH1 mutations in adult T-cell acute lymphoblastic leukemia

Li,Min; Xiao,Lichan; Xu,Jingyan; Zhang,Run; Guo,Jingjing; Olson,Justin; Wu,Yujie; Li,Jianyong; Song,Chunhua; Ge,Zheng

doi:10.3892/ol.2016.4581

July-2016 Volume 12 Issue 1

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

July-2016 Volume 12 Issue 1

Full Size Image

Article Open Access

Co‑existence of PHF6 and NOTCH1 mutations in adult T-cell acute lymphoblastic leukemia

Authors:
- Min Li
- Lichan Xiao
- Jingyan Xu
- Run Zhang
- Jingjing Guo
- Justin Olson
- Yujie Wu
- Jianyong Li
- Chunhua Song
- Zheng Ge
View Affiliations / Copyright

Affiliations: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu 210029, P.R. China, Department of Hematology, The Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing, Jiangsu 210008, P.R. China, Department of Hematology, The Second Hospital of Nanjing, Nanjing, Jiangsu 320100, P.R. China, Department of Biology, University of Wisconsin‑Stout, Menomonie, WI 54751, USA, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA

Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Pages: 16-22
|
Published online on: May 16, 2016

https://doi.org/10.3892/ol.2016.4581
Expand metrics +

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) results from the collaboration of multiple genetic abnormalities in the transformation of T-cell progenitors. Plant homeodomain finger protein 6 (PHF6) has recently been established as a key tumor suppressor, which is mutated in T‑ALL; however, the clinical significance of PHF6 mutations has not been fully determined in adult T‑ALL. In the present study, amplification of the PHF6 exons was performed, followed by DNA sequencing to identify the genomic mutations and examine the expression of PHF6 in adult patients with T‑ALL. The correlation between PHF6 mutations and clinical features was also analyzed using a χ2 test, and between PHF6 mutations and survival curve using the Kaplan‑Meier methods. PHF6 mutations were detected in 27.1% of the Chinese adults with T‑ALL (16/59), 10 of which were found to be novel mutations. A significantly lower expression level of PHF6 was observed in T-ALL patients with PHF6 mutations compared with those without mutations. Of the observed mutations in PHF6, 6/16 were frame‑shift mutations, indicating a PHF6 dysfunction in those patients. Of note, PHF6 mutations were found to be significantly associated with older age, lower hemoglobin levels, higher frequency of CD13 positivity and higher incidence of splenomegaly or lymphadenopathy. Furthermore, PHF6 mutations were found to be significantly correlated with Notch homolog 1, translocation‑associated (Drosophila) (NOTCH1) mutations. The patients with T‑ALL with co‑existence of the two mutations had a significantly shorter event‑free survival and a poor prognosis. The present results indicated that PHF6 is inactivated in adult T‑ALL, due to its low expression and mutations. The present data indicated the synergistic effect of PHF6 and NOTCH1 mutations, as well as their co‑existence, on the oncogenesis of adult T-ALL, and their potential as a prognostic marker for the disease.

View Figures

View References

1	Graux C, Cools J, Michaux L, Vandenberghe P and Hagemeijer A: Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: From thymocyte to lymphoblast. Leukemia. 20:1496–1510. 2006. View Article : Google Scholar : PubMed/NCBI
2	Mullighan CG and Downing JR: Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: Recent insights and future directions. Leukemia. 23:1209–1218. 2009. View Article : Google Scholar : PubMed/NCBI
3	Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, et al: The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 481:157–163. 2012. View Article : Google Scholar : PubMed/NCBI
4	Della Gatta G, Palomero T, Perez-Garcia A, Ambesi-Impiombato A, Bansal M, Carpenter ZW, De Keersmaecker K, Sole X, Xu L, Paietta E, et al: Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nat Med. 18:436–440. 2012. View Article : Google Scholar : PubMed/NCBI
5	Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N, De Moerloose B, Philippé J, González-García S, Toribio ML, et al: PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet. 42:338–342. 2010. View Article : Google Scholar : PubMed/NCBI
6	Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, Schelley S, Hoyme HE, White SM, Delatycki MB, et al: Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome. Nat Genet. 32:661–665. 2002. View Article : Google Scholar : PubMed/NCBI
7	Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, Nicolas C, Payer AR, Fernandez HF, Tallman MS, et al: PHF6 mutations in adult acute myeloid leukemia. Leukemia. 25:130–134. 2011. View Article : Google Scholar : PubMed/NCBI
8	Wang Q, Qiu H, Jiang H, Wu L, Dong S, Pan J, Wang W, Ping N, Xia J, Sun A, et al: Mutations of PHF6 are associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214 in T-cell acute lymphoblastic leukemia. Haematologica. 96:1808–1814. 2011. View Article : Google Scholar : PubMed/NCBI
9	Lin ZK, Zhang R, Ge Z, Liu J, Guo X, Qiao C, Wu YJ, Qiu HR, Zhang JF and Li JY: Characteristics of NOTCH1 mutation in adult T-cell acute lymphoblastic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 21:1403–1408. 2013.(In Chinese). PubMed/NCBI
10	Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J and Vardiman JW: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (4th). IARC press. Lyon: 2008.
11	Guo X, Zhang R, Liu J, Li M, Song C, Dovat S, Li J and Ge Z: Characterization of LEF1 high expression and novel mutations in adult acute lymphoblastic leukemia. PLoS One. 10:e01254292015. View Article : Google Scholar : PubMed/NCBI
12	Guo X, Zhang R, Ge Z, Xu JY, Li M, Qiao C, Qiu HR and Li JY: Mutations of FBXW7 in adult T-Cell acute lymphocytic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 23:612–618. 2015.(In Chinese). PubMed/NCBI
13	Shaffer LG, Slovak ML and Campbell LJ: An International System for Human Cytogenetic Nomenclature. Recommendations of the International Standing Committee on Human Cytogenetic Nomenclature. Karger S.AG: (Basel, Switzerland). 2009.

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Co‑existence of PHF6 and NOTCH1 mutations in adult T-cell acute lymphoblastic leukemia

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Related Articles