Research Article: GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy

Date Published: January 23, 2017

Publisher: Public Library of Science

Author(s): Li Yang, Hanxiao Sun, Yanan Cao, Binbin Xuan, Yingchao Fan, Huiming Sheng, Wenfang Zhuang, Javier S Castresana.

http://doi.org/10.1371/journal.pone.0170630

Abstract

Drug resistance constitutes one of the main obstacles for clinical recovery of acute myeloid leukemia (AML) patients. Therefore, the treatment of AML requires new strategies, such as adding a third drug. To address whether GATA2 could act as a regulator of chemotherapy resistance in human leukemia cells, we observed KG1a cells and clinical patients’ AML cells with a classic drug (Cerubidine) and Gefitinib. After utilizing chemotherapy, the expression of GATA2 and its target genes (EVI, SCL and WT1) in surviving AML cells and KG1a cells were significantly enhanced to double and quadrupled compared to its original level respectively. Furthermore, with continuous chemotherapeutics, AML cells with GATA2 knockdown or treated with GATA2 inhibitor (K1747) almost eliminated with dramatically reduced expression of WT1, SCL, EVI, and significantly increased apoptotic population. Therefore, we propose that reducing GATA2 expression or inhibition of its transcription activity can relieve the drug resistance of acute myeloid leukemia cells and it would be helpful for eliminating the leukemia cells in patients.

Partial Text

Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous malignancy that is primarily treated with chemotherapy, targeted therapy, immune regulation therapy and bone marrow transplant [1, 2]. Considerable progresses have been made in the treatment of AML with application of combined chemotherapies during recent years, which manifested as improved complete remission and long-term survival rates. However, problems such as the resistance to chemotherapies and serious adverse reaction during the process of chemotherapies remain to be tackled in AML treatment[2], in which major cause of treatment failure is resistance to cytarabine (ara-C) and anthracycline [e.g., daunorubicin (DNR)]-based chemotherapy[3]. Thus, novel strategies such small molecular medicines and addition of a third drug are needed to overcome chemoresistance and improve the overall survival of AML patients[4].

Recently, GATA2 is proved to be required for the survival of RAS pathway mutated non-small cell lung cancer (NSCLC) cells [23], and it has identified that GATA2 as a regulator of chemotherapy resistance and tumorigenicity in lethal prostate cancer through experimental models and clinical databases [24]. While GATA2 has long been implicated as a hematopoietic transcription factor and its dysregulated expression is associated with human immunodeficiency syndromes and vascular integrity [25], thus, the regulate effect of GATA2 observed in solid tumors may have similar effect on human leukemia cells to chemotherapy. To address whether the effect could be replicated in human leukemia cells, we oberserved KG1a cells and clinical patients’ AML cells with a classic drug (Cerubidine) and Gefitinib [26, 27].

 

Source:

http://doi.org/10.1371/journal.pone.0170630