Plant homeodomain finger protein 2 as a novel IKAROS target in acute lymphoblastic leukemia

Abstract

Aim: Clinical significance of plant homeodomain finger 2 (PHF2) expressions is explored in acute lymphoblastic leukemia (ALL) patients. Methods: mRNA level was examined by qPCR. The retroviral gene expression, shRNA knockdown and chromatin-immunoprecipitation are used to observe IKAROS regulation on PHF2 transcription. Results:PHF2 expression is significantly reduced in subsets of ALL patients, and PHF2^low expression correlates with leukemia cell proliferation and an elevation of several poor prognostic markers in B-cell ALL. IKAROS directly promotes PHF2 expression and patients with IKAROS deletion have significantly lower PHF2 expression. Casein kinase II (CK2) inhibitor significantly promotes PHF2 expression in an IKAROS-dependent manner, and casein kinase II inhibitor treatment also results in an increase of PHF2 expression and enrichment of IKAROS and H3K4me3 at PHF2 promoter in primary cells. Conclusion: Our results demonstrate that the IKAROS promotes PHF2 expression, and suggest that PHF2^low expression works with the IKAROS gene deletion to drive oncogenesis of ALL.

Keywords::

• acute lymphoblastic leukemia
• histone modification
• IKZF1
• PHF2

Acknowledgements

The authors thank J Koster, University of Amsterdam, the Netherlands for approval of use of microarray data on ‘R2: Genomics Analysis and Visualization Platform’ (http://r2.amc.nl).

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/full/10.2217/epi-2017-0092

Availability of data&materials

The datasets generated from the patients during the current study are not publicly available in accordance with local health research ethics protocols but may be available from the corresponding author.

Authors’ contribution

Z Ge, Y Gu, Q Han, Q Ge, G Gao, J Ma, H Song, J Hu, B Chen, S Dovat, C Song performed experiments and analyzed data; C Song, Z Ge, S Dovat designed and supervised data analysis; C Song, Z Ge, J Sloane, G Gao wrote the manuscript.

Financial&competing interests disclosure

This work is supported in part by Milstein Medical Asian American Partnership (MMAAP) Foundation Research Project Award in Hematology (2017); The National Natural Science Foundation of China (81770172, 81270613); The Key Research&Technology Projects in Jiangsu Province (BE2017747); The Fundamental Research Funds for the Central Universities (2242017K40271, 2242016K40143); Jiangsu Province Key Medical Talents (RC2011077); The Scientific Research Foundation for the Returned Overseas Chinese Scholars; State Education Ministry (39th); China Postdoctoral Science Foundation (20090461134); Special grade of the financial support from China Postdoctoral Science Foundation (201003598); The Six Great Talent Peak Plan of Jiangsu (2010-WS-024) (to Z Ge). This work has also been partially supported by NIH, National Cancer Institute grants (R01CA209829, R01CA213912), Hyundai Hope on Wheels Scholar Grant, the Four Diamonds Fund of the Pennsylvania State University College of Medicine (to S Dovat and C Song); Bear Necessities Pediatric Cancer Foundation, Alex’s Lemonade Stand Foundation and the John Wawrynovic Leukemia Research Scholar Endowment (to S Dovat). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

All the patients provided their written informed consent in accordance with the Declaration of Helsinki before enrollment in the study. The study was approved by the Institutional Review Board of the Nanjing Medical University and Zhongda Hospital Southeast University, Nanjing, China.

Additional information

Funding

This work is supported in part by Milstein Medical Asian American Partnership (MMAAP) Foundation Research Project Award in Hematology (2017); The National Natural Science Foundation of China (81770172, 81270613); The Key Research&Technology Projects in Jiangsu Province (BE2017747); The Fundamental Research Funds for the Central Universities (2242017K40271, 2242016K40143); Jiangsu Province Key Medical Talents (RC2011077); The Scientific Research Foundation for the Returned Overseas Chinese Scholars; State Education Ministry (39th); China Postdoctoral Science Foundation (20090461134); Special grade of the financial support from China Postdoctoral Science Foundation (201003598); The Six Great Talent Peak Plan of Jiangsu (2010-WS-024) (to Z Ge). This work has also been partially supported by NIH, National Cancer Institute grants (R01CA209829, R01CA213912), Hyundai Hope on Wheels Scholar Grant, the Four Diamonds Fund of the Pennsylvania State University College of Medicine (to S Dovat and C Song); Bear Necessities Pediatric Cancer Foundation, Alex’s Lemonade Stand Foundation and the John Wawrynovic Leukemia Research Scholar Endowment (to S Dovat). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.